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Journal articles on the topic 'Guanylate cyclase, retinal dystrophy'

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Published: 9 March 2023

Last updated: 10 March 2023

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1

Downes, Susan M. "Autosomal Dominant Cone-Rod Dystrophy With Mutations in the Guanylate Cyclase 2D Gene Encoding Retinal Guanylate Cyclase-1." Archives of Ophthalmology 119, no. 11 (November 1, 2001): 1667. http://dx.doi.org/10.1001/archopht.119.11.1667.

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2

Marino, Valerio, Giuditta Dal Cortivo, Paolo Enrico Maltese, Giorgio Placidi, Elisa De Siena, Benedetto Falsini, Matteo Bertelli, and Daniele Dell’Orco. "Impaired Ca2+ Sensitivity of a Novel GCAP1 Variant Causes Cone Dystrophy and Leads to Abnormal Synaptic Transmission Between Photoreceptors and Bipolar Cells." International Journal of Molecular Sciences 22, no. 8 (April 14, 2021): 4030. http://dx.doi.org/10.3390/ijms22084030.

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Guanylate cyclase-activating protein 1 (GCAP1) is involved in the shutdown of the phototransduction cascade by regulating the enzymatic activity of retinal guanylate cyclase via a Ca2+/cGMP negative feedback. While the phototransduction-associated role of GCAP1 in the photoreceptor outer segment is widely established, its implication in synaptic transmission to downstream neurons remains to be clarified. Here, we present clinical and biochemical data on a novel isolate GCAP1 variant leading to a double amino acid substitution (p.N104K and p.G105R) and associated with cone dystrophy (COD) with an unusual phenotype. Severe alterations of the electroretinogram were observed under both scotopic and photopic conditions, with a negative pattern and abnormally attenuated b-wave component. The biochemical and biophysical analysis of the heterologously expressed N104K-G105R variant corroborated by molecular dynamics simulations highlighted a severely compromised Ca2+-sensitivity, accompanied by minor structural and stability alterations. Such differences reflected on the dysregulation of both guanylate cyclase isoforms (RetGC1 and RetGC2), resulting in the constitutive activation of both enzymes at physiological levels of Ca2+. As observed with other GCAP1-associated COD, perturbation of the homeostasis of Ca2+ and cGMP may lead to the toxic accumulation of second messengers, ultimately triggering cell death. However, the abnormal electroretinogram recorded in this patient also suggested that the dysregulation of the GCAP1–cyclase complex further propagates to the synaptic terminal, thereby altering the ON-pathway related to the b-wave generation. In conclusion, the pathological phenotype may rise from a combination of second messengers’ accumulation and dysfunctional synaptic communication with bipolar cells, whose molecular mechanisms remain to be clarified.

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3

Kelsell, R. E., K. Gregory-Evans, A. M. Payne, I. Perrault, J. Kaplan, R. B. Yang, D. L. Garbers, A. C. Bird, A. T. Moore, and D. M. Hunt. "Mutations in the Retinal Guanylate Cyclase (RETGC-1) Gene in Dominant Cone-Rod Dystrophy." Human Molecular Genetics 7, no. 7 (July 1, 1998): 1179–84. http://dx.doi.org/10.1093/hmg/7.7.1179.

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4

Mahroo, Omar A., Gavin Arno, Rola Ba-Abbad, Susan M. Downes, Alan Bird, and Andrew R. Webster. "Reanalysis of Association of Pro50Leu Substitution in Guanylate Cyclase Activating Protein-1 With Dominant Retinal Dystrophy." JAMA Ophthalmology 138, no. 2 (February 1, 2020): 200. http://dx.doi.org/10.1001/jamaophthalmol.2019.4959.

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5

Martínez-Velázquez, Luis A., and Niels Ringstad. "Antagonistic regulation of trafficking to Caenorhabditis elegans sensory cilia by a Retinal Degeneration 3 homolog and retromer." Proceedings of the National Academy of Sciences 115, no. 3 (December 27, 2017): E438—E447. http://dx.doi.org/10.1073/pnas.1712302115.

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Sensory neurons often possess cilia with elaborate membrane structures that are adapted to the sensory modality of the host cell. Mechanisms that target sensory transduction proteins to these specialized membrane domains remain poorly understood. Here, we show that a homolog of the human retinal dystrophy gene Retinal Degeneration 3 (RD3) is a Golgi-associated protein required for efficient trafficking of a sensory receptor, the receptor-type guanylate cyclase GCY-9, to cilia in chemosensory neurons of the nematode Caenorhabditis elegans. The trafficking defect caused by mutation of the nematode RD3 homolog is suppressed in vivo by mutation of key components of the retromer complex, which mediates recycling of cargo from endosomes to the Golgi. Our data show that there exists a critical balance in sensory neurons between the rates of anterograde and retrograde trafficking of cargo destined for the sensory cilium and this balance requires molecular specialization at an early stage of the secretory pathway.

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6

Payne, Annette M., Susan M. Downes, David A. R. Bessant, Catherine Plant, Tony Moore, Alan C. Bird, and Shomi S. Bhattacharya. "Genetic analysis of the guanylate cyclase activator 1B (GUCA1B) gene in patients with autosomal dominant retinal dystrophies: Table 1." Journal of Medical Genetics 36, no. 9 (September 1, 1999): 691–93. http://dx.doi.org/10.1136/jmg.36.9.691.

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The guanylate cyclase activator proteins (GCAP1 and GCAP2) are calcium binding proteins which by activating Ret-GC1 play a key role in the recovery phase of phototransduction. Recently a mutation in theGUCA1A gene (coding for GCAP1) mapping to the 6p21.1 region was described as causing cone dystrophy in a British family. In addition mutations in Ret-GC1have been shown to cause Leber congenital amaurosis and cone-rod dystrophy. To determine whether GCAP2 is involved in dominant retinal degenerative diseases, the GCAP2 gene was screened in 400 unrelated subjects with autosomal dominant central and peripheral retinal dystrophies.A number of changes involving the intronic as well as the coding sequence were observed. In exon 1 a T to C nucleotide change was observed leaving the tyrosine residue 57 unchanged. In exon 3 a 1 bp intronic insertion, a single nucleotide substitution G to A in the intron 3′ of this exon, and a GAG to GAT change at codon 155 were observed. This latter change results in a conservative change of glutamic acid to aspartic acid. In exon 4 a 7 bp intronic insertion, a single nucleotide A to G substitution in the intron 5′ of this exon, and a single base pair change C to G in the intron 3′ of exon 4 were seen. None of these changes would be expected to affect correct splicing of this gene. All these changes were observed in controls. The results of this study do not show any evidence so far that GCAP2 is involved in the pathogenesis of autosomal dominant retinal degeneration in this group of patients. All the changes detected were found to be sequence variations or polymorphisms and not disease causing.

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7

Biasi, Amedeo, Valerio Marino, Giuditta Dal Cortivo, Paolo Enrico Maltese, Antonio Mattia Modarelli, Matteo Bertelli, Leonardo Colombo, and Daniele Dell’Orco. "A Novel GUCA1A Variant Associated with Cone Dystrophy Alters cGMP Signaling in Photoreceptors by Strongly Interacting with and Hyperactivating Retinal Guanylate Cyclase." International Journal of Molecular Sciences 22, no. 19 (October 6, 2021): 10809. http://dx.doi.org/10.3390/ijms221910809.

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Guanylate cyclase-activating protein 1 (GCAP1), encoded by the GUCA1A gene, is a neuronal calcium sensor protein involved in shaping the photoresponse kinetics in cones and rods. GCAP1 accelerates or slows the cGMP synthesis operated by retinal guanylate cyclase (GC) based on the light-dependent levels of intracellular Ca2+, thereby ensuring a timely regulation of the phototransduction cascade. We found a novel variant of GUCA1A in a patient affected by autosomal dominant cone dystrophy (adCOD), leading to the Asn104His (N104H) amino acid substitution at the protein level. While biochemical analysis of the recombinant protein showed impaired Ca2+ sensitivity of the variant, structural properties investigated by circular dichroism and limited proteolysis excluded major structural rearrangements induced by the mutation. Analytical gel filtration profiles and dynamic light scattering were compatible with a dimeric protein both in the presence of Mg2+ alone and Mg2+ and Ca2+. Enzymatic assays showed that N104H-GCAP1 strongly interacts with the GC, with an affinity that doubles that of the WT. The doubled IC50 value of the novel variant (520 nM for N104H vs. 260 nM for the WT) is compatible with a constitutive activity of GC at physiological levels of Ca2+. The structural region at the interface with the GC may acquire enhanced flexibility under high Ca2+ conditions, as suggested by 2 μs molecular dynamics simulations. The altered interaction with GC would cause hyper-activity of the enzyme at both low and high Ca2+ levels, which would ultimately lead to toxic accumulation of cGMP and Ca2+ in the photoreceptor outer segment, thus triggering cell death.

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8

Avesani, Anna, Valerio Marino, Serena Zanzoni, Karl-Wilhelm Koch, and Daniele Dell'Orco. "Molecular properties of human guanylate cyclase–activating protein 2 (GCAP2) and its retinal dystrophy–associated variant G157R." Journal of Biological Chemistry 296 (January 2021): 100619. http://dx.doi.org/10.1016/j.jbc.2021.100619.

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9

Marino, Valerio, Alexander Scholten, Karl-Wilhelm Koch, and Daniele Dell'Orco. "Two retinal dystrophy-associated missense mutations inGUCA1Awith distinct molecular properties result in a similar aberrant regulation of the retinal guanylate cyclase." Human Molecular Genetics 24, no. 23 (September 10, 2015): 6653–66. http://dx.doi.org/10.1093/hmg/ddv370.

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10

Abbas, Seher, Valerio Marino, Laura Bielefeld, Karl-Wilhelm Koch, and Daniele Dell’Orco. "Constitutive Activation of Guanylate Cyclase by the G86R GCAP1 Variant Is Due to “Locking” Cation-π Interactions that Impair the Activator-to-Inhibitor Structural Transition." International Journal of Molecular Sciences 21, no. 3 (January 23, 2020): 752. http://dx.doi.org/10.3390/ijms21030752.

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Guanylate Cyclase activating protein 1 (GCAP1) mediates the Ca2+-dependent regulation of the retinal Guanylate Cyclase (GC) in photoreceptors, acting as a target inhibitor at high [Ca2+] and as an activator at low [Ca2+]. Recently, a novel missense mutation (G86R) was found in GUCA1A, the gene encoding for GCAP1, in patients diagnosed with cone-rod dystrophy. The G86R substitution was found to affect the flexibility of the hinge region connecting the N- and C-domains of GCAP1, resulting in decreased Ca2+-sensitivity and abnormally enhanced affinity for GC. Based on a structural model of GCAP1, here, we tested the hypothesis of a cation-π interaction between the positively charged R86 and the aromatic W94 as the main mechanism underlying the impaired activator-to-inhibitor conformational change. W94 was mutated to F or L, thus, resulting in the double mutants G86R+W94L/F. The double mutants showed minor structural and stability changes with respect to the single G86R mutant, as well as lower affinity for both Mg2+ and Ca2+, moreover, substitutions of W94 abolished “phase II” in Ca2+-titrations followed by intrinsic fluorescence. Interestingly, the presence of an aromatic residue in position 94 significantly increased the aggregation propensity of Ca2+-loaded GCAP1 variants. Finally, atomistic simulations of all GCAP1 variants in the presence of Ca2+ supported the presence of two cation-π interactions involving R86, which was found to act as a bridge between W94 and W21, thus, locking the hinge region in an activator-like conformation and resulting in the constitutive activation of the target under physiological conditions.

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11

Roth, Nora, Christoph Faul, Christiane Dorn, Wichard Vogel, Wolfgang A. Bethge, Lothar Kanz, Hans-Georg Rammensee, and Sebastian P. Haen. "Development of New Autoimmunity Against T Cell Antigens Derived From Retinal Proteins After Allogeneic Hematopoietic Cell Transplantation." Blood 120, no. 21 (November 16, 2012): 3060. http://dx.doi.org/10.1182/blood.v120.21.3060.3060.

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Abstract Abstract 3060 Introduction: Graft versus host disease (GvHD) is mainly mediated by T cells recognizing major (MHC) and minor (miHAG) histocompatibility antigens (human leukocyte antigens and MHC-restricted epitopes, respectively). The clinical appearance of a GvHD affecting the central nervous system (CNS) and the retina as part of the CNS is rare and evidence is limited to single case reports. Some publications describe the development of new autoimmunity after hematopoietic cell transplantation (HCT) manifested as hemolytic anemia (AIHA), immune thrombocytopenia (ITP) or myasthenia gravis. Of note, new autoinflammatory diseases affecting the retina have not been reported. In this study we investigated the GvHD of the retina and examined the development of new autoimmune T cell responses against epitopes derived from proteins exclusively expressed in the retina. Patients and Methods: We analyzed T cells from 8 women and 12 men with a median age of 55 years (range 29 – 69 years) that had underwent HCT. Underlying diseases were acute lymphoblastic leukemia (n = 1), acute myeloid leukemia, (n = 6), chronic myeloid leukemia (n = 1), myelodysplastic syndrome (n = 3), myeloproliferative syndromes (primary myelofibrosis, n = 2; essential thrombocytemia with secondary myelofibrosis, n = 2; polycythemia vera with secondary myelofibrosis, n = 1), B-cell non-Hodgkin lymphoma (gray zone lymphoma, n = 1; follicular lymphoma, n = 1; peripheral T cell lymphoma, n = 1) and Hodgkin's lymphoma (n = 1). Potential T cell epitopes from four unique highly polymorphic retinal proteins (membrane-bound retinal guanylate cyclase 1 protein (retGC), the guanylate cyclase activating proteins 1 and 2 (GCAP1 and GCAP2) and the retinoid binding protein 3 (RBP3)) were identified using 2 approaches. First, genomic DNA derived from both donor and recipient coding for these proteins was sequenced by Sanger sequencing in search of single nucleotide polymorphisms (SNP). Second, alternate peptide expression based on known SNP was predicted using internet based databases (EpiToolKit). The predicted epitopes were synthesized and used in T cell assays. Peripheral blood mononuclear cells (PBMCs) from patients after hematopoietic regeneration (neutrophils > 500/μl) were stimulated with SNP peptide pairs (peptides pairs differing in one amino acid) and analyzed by IFNg-ELISPOT and flow cytometry. Results: In 5 out of 20 patients (25%), strong T cell responses against peptides derived from retGC as well as from GCAP1 and GCAP2 were observed which were not detectable before HCT and not reflected by a difference in the DNA sequence between donor and recipient. Two patients of the cohort presented with visual loss which was due to cone dystrophy (n = 1) and retrobulbar optic neuritis (n = 1). In the patient with cone dystrophy, we observed circulating antigen specific T cells against peptides derived from retGC. The patient with retrobulbar optic neuritis did not have antigen specific T cell responses. In 2 clinically silent patients, we found IFNg producing CD4+ T cells that recognized a predicted GCAP1-derived self-peptide. One patient also had a strong T cell response against a GCAP2-derived self-peptide. The T cells specifically recognized the peptide represented in the autologous DNA sequence; no reactivity was seen after stimulation with the SNP peptide. Furthermore, the T cell reactions persisted over time and were still detectable one year after HCT. In another patient, T cell responses against the pair of GCAP2 peptides were detected. Here, the reactivity against one peptide could not be discriminated due to limited availability of patient T cells. One further patient displayed T cell responses against GCAP and retGC peptides, which were directed against both self- and SNP peptides. As controls we stimulated T cells from 5 HLA-matched healthy individuals with all respective peptides and observed no T cell reaction. Conclusions: 25% of the patients revealed strong T cell responses against retinal autoantigens after HCT. T cell responses detected late after HCT as observed in 3 patients might indicate a chronic antigen exposure. Clinical manifestations were cone dystrophy (here, antigen-specific T cells against cone protein-derived peptides could be detected) and retrobulbar optic neuritis. To our knowledge, this is the first report on antigen-specificity of neoautoinflammatory cells after allogeneic HCT. Disclosures: No relevant conflicts of interest to declare.

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12

Smith, M., N. Whittock, A. Searle, M. Croft, C. Brewer, and M. Cole. "Phenotype of autosomal dominant cone–rod dystrophy due to the R838C mutation of the GUCY2D gene encoding retinal guanylate cyclase-1." Eye 21, no. 9 (October 13, 2006): 1220–25. http://dx.doi.org/10.1038/sj.eye.6702612.

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13

Kamenarova, Kunka, Marta Corton, Blanca García-Sandoval, Patricia Fernández-San Jose, Valentin Panchev, Almudena Ávila-Fernández, Maria Isabel López-Molina, Christina Chakarova, Carmen Ayuso, and Shomi S. Bhattacharya. "NovelGUCA1AMutations Suggesting Possible Mechanisms of Pathogenesis in Cone, Cone-Rod, and Macular Dystrophy Patients." BioMed Research International 2013 (2013): 1–15. http://dx.doi.org/10.1155/2013/517570.

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Here, we report two novelGUCA1A(the gene for guanylate cyclase activating protein 1) mutations identified in unrelated Spanish families affected by autosomal dominant retinal degeneration (adRD) with cone and rod involvement. All patients from a three-generation adRD pedigree underwent detailed ophthalmic evaluation. Total genome scan using single-nucleotide polymorphisms and then the linkage analysis were undertaken on the pedigree. Haplotype analysis revealed a 55.37 Mb genomic interval cosegregating with the disease phenotype on chromosome 6p21.31-q15. Mutation screening of positional candidate genes found a heterozygous transition c.250C>T in exon 4 ofGUCA1A, corresponding to a novel mutation p.L84F. A second missense mutation, c.320T>C (p.I107T), was detected by screening of the gene in a Spanish patients cohort. Using bioinformatics approach, we predicted that either haploinsufficiency or dominant-negative effect accompanied by creation of a novel function for the mutant protein is a possible mechanism of the disease due to c.250C>T and c.320T>C. Although additional functional studies are required, our data in relation to the c.250C>T mutation open the possibility thattransacting factors binding to de novo created recognition site resulting in formation of aberrant splicing variant is a disease model which may be more widespread than previously recognized as a mechanism causing inherited RD.

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14

Weigell-Weber, Maike. "Codons 837 and 838 in the Retinal Guanylate Cyclase Gene on Chromosome 17p: Hot Spots for Mutations in Autosomal Dominant Cone-Rod Dystrophy?" Archives of Ophthalmology 118, no. 2 (February 1, 2000): 300. http://dx.doi.org/10.1001/archopht.118.2.300.

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15

Wilkie, S. E. "Functional characterization of missense mutations at codon 838 in retinal guanylate cyclase correlates with disease severity in patients with autosomal dominant cone-rod dystrophy." Human Molecular Genetics 9, no. 20 (December 1, 2000): 3065–73. http://dx.doi.org/10.1093/hmg/9.20.3065.

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16

Gregory-Evans, Kevin, Rosemary E. Kelsell, Cheryl Y. Gregory-Evans, Susan M. Downes, Fred W. Fitzke, Graham E. Holder, Matthew Simunovic, et al. "Autosomal dominant cone–rod retinal dystrophy (CORD6) from heterozygous mutation of GUCY2D , which encodes retinal guanylate cyclase 1 1The authors have no proprietary interests in the materials mentioned in the study." Ophthalmology 107, no. 1 (January 2000): 55–61. http://dx.doi.org/10.1016/s0161-6420(99)00038-x.

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17

Veske, Andres, Sven Erik G. Nilsson, and Andreas Gal. "Organization of the canine gene encoding the E isoform of retinal guanylate cyclase (cGC-E) and exclusion of its involvement in the inherited retinal dystrophy of the Swedish Briard and Briard–Beagle dogs." Biochimica et Biophysica Acta (BBA) - Biomembranes 1372, no. 1 (June 1998): 69–77. http://dx.doi.org/10.1016/s0005-2736(98)00047-9.

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18

Mirza, Nora, Manfred Zierhut, Andreas Korn, Antje Bornemann, Christoph Simon, Annika Boehm, Wolfgang A. Bethge, Lothar Kanz, Hans-Georg Rammensee, and Sebastian P. Haen. "Self-Peptide Recognition of Posterior Eye Segment Epitopes Mediated By Allogeneic T Cells in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation." Blood 124, no. 21 (December 6, 2014): 1173. http://dx.doi.org/10.1182/blood.v124.21.1173.1173.

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Abstract Graft versus Host Disease (GvHD) is the major complication of allogeneic hematopoetic cell transplantation (HCT). It mostly affects the gastrointestinal tract, skin or liver, but may also involve the central nervous system (CNS). Although GvHD is believed to be mainly mediated by T cells recognizing HLA mismatches or minor histocompatibility antigens (MHC-restricted peptides differing in single amino acids based on protein sequence variants between donor and recipient due to genetic differences), limited evidence is known about the exact MHC-restricted T cell epitopes recognized on recipient cells. In this study, we evaluated the clinical manifestation of GvHD in the posterior eye segment (PS) as part of the CNS and characterized self-antigens mediating reactivity of allogeneic T cells. The first patient group comprised 6 individuals (3 women and 3 men, median age 40 years, range 20-58 years) with diseases of the PS after HCT. Diseases were ALL (n=4), AML (n=1) and MPS (n=1). 8 transplantations (1-2 per patient) were performed using grafts from matched related (MRD, n=1), matched unrelated (MUD, n=4), mismatched unrelated (MMUD, n=2) or haploidentical (n=1) donors. The second group included 22 patients (7 women and 15 men, median age 55 years, range 29-69 years) irrespective of ocular symptoms recruited before HCT. Diseases were AML (n=7), CML (n=1), MDS (n=4), MPS (n=5), multiple myeloma (n=1) and lymphoma (n=4). All patients received grafts from HLA-identical donors (MRD n=7, MUD n=15). GvHD prophylaxis was performed using standard protocols. Peripheral blood mononuclear cells (PBMC) and DNA were isolated from blood samples. Autologous cell samples were blood samples before or oral mucosa after HCT. Allogeneic cells were obtained from patients with complete donor chimerism. DNA sequencing was performed to identify donor-recipient single nucleotide polymorphisms (SNP). Retina specific candidate epitopes derived from the retinal guanylate cyclase 2D (GUCY2D), the retinoid binding protein (RBP) and the guanylate cyclase activating proteins A1 und B1 (GUCA1A/GUCA1B) were predicted based on known SNP and individual protein sequences using the database EpiToolKit. PBMC were prestimulated with both wildtype and SNP peptides. T cell reactivity was determined in ELISpot and intracellular cytokine staining. Moreover, T cells from 5 family donors were evaluated. All epitopes were evaluated in at least 8 healthy individuals carrying the respective HLA-subtype. Immunogenicity of MHC-I restricted candidate epitopes was determined in in vitro priming. PS diagnoses were optical atrophy (n=2), in 1 case combined with a selective dysfunction of the cones, optic neuritis (n=2), anemic retinopathy (n=1) and VZV retinitis (n=1). In two of these patients (one with selective cone dystrophy, the other with VZV retinitis) antigen specific T cells against MHC-II restricted GUCY2D epitopes could be detected 24 and 40 months after HCT. DNA sequencing did not reveal a SNP indicating recognition of self-antigens. In 6/22 patients without PS symptoms, retina-specific T cells could be detected, here directed against MHC-II restricted epitopes derived from GUCA1A (n=3), GUCA1B (n=3) and GUCY2D (n=3) between 4 and 14 months after HCT. After stimulation with the variant peptide, no T cell reactivity occurred, confirming that the observed responses were sequence specific. T cell responses tended to increase over time but could disappear at certain time points. Again, no SNP could be observed. Hence, T cell reactivity was directed against self-epitopes. Transplantation of retina-antigen specific cells and cross-reactivity against naturally occurring epitopes were excluded since no reactivity could be detected in donor samples and healthy individuals. In in vitro priming experiments, 36/55 of MHC-I restricted peptides could be confirmed as T cell epitopes. Thus, GvHD manifestations of the retina can be detected in patients after allogeneic HCT and can be mediated by antigen-specific T cells. Development of PS GvHD may be triggered by viral infections and should be considered in case of atypical ophthalmologic findings. The antigens recognized hereby can be self-antigens and do not need to be based on genetic differences between donor and recipient. In summary, recognition of self-antigens by allogeneic T cells represents a novel pathomechanism of graft-host-interaction in patients undergoing allogeneic HCT. Disclosures No relevant conflicts of interest to declare.

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Pugh, Edward N., Teresa Duda, Ari Sitaramayya, and Rameshwar K. Sharma. "Photoreceptor Guanylate Cyclases: A Review." Bioscience Reports 17, no. 5 (October 1, 1997): 429–73. http://dx.doi.org/10.1023/a:1027365520442.

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Almost three decades of research in the field of photoreceptor guanylate cyclases are discussed in this review. Primarily, it focuses on the members of membrane-bound guanylate cyclases found in the outer segments of vertebrate rods. These cyclases represent a new guanylate cyclase subfamily, termed ROS-GC, which distinguishes itself from the peptide receptor guanylate cyclase family that it is not extracellularly regulated. It is regulated, instead, by the intracellularly-generated Ca2+ signals. A remarkable feature of this regulation is that ROS-GC is a transduction switch for both the low and high Ca2+ signals. The low Ca2+ signal transduction pathway is linked to phototransduction, but the physiological relevance of the high Ca2+ signal transduction pathway is not yet clear; it may be linked to neuronal synaptic activity. The review is divided into eight sections. In Section I, the field of guanylate cyclase is introduced and the scope of the review is briefly explained; Section II covers a brief history of the investigations and ideas surrounding the discovery of rod guanylate cyclase. The first five subsections of Section III review the experimental efforts to quantify the guanylate cyclase activity of rods, including in vitro and in situ biochemistry, and also the work done since 1988 in which guanylate cyclase activity has been determined. In the remaining three subsections an analytical evaluation of the Ca2+ modulation of the rod guanylate cyclase activity related to phototransduction is presented. Section IV deals with the issues of a biochemical nature: isolation and purification, subcellular localization and functional properties of rod guanylate cyclase. Section V summarizes work on the cloning of the guanylate cyclases, analysis of their primary structures, and determination of their location with in situ hybridization. Section VI summarizes studies on the regulation of guanylate cyclases, with a focus on guanylate cyclases activating proteins. In Section VII, the evidence about the localization and functional role of guanylate cyclases in other retinal cells, especially in “on-bipolar” cells, in which guanylate cyclase most likely plays a critical role in electrical signaling, is discussed. The review concludes with Section VIII, with remarks about the future directions of research on retinal guanylate cyclases.

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20

Yamazaki, Akio, Matsuyo Yamazaki, Russell K. Yamazaki, and Jiro Usukura. "Illuminated Rhodopsin Is Required for Strong Activation of Retinal Guanylate Cyclase by Guanylate Cyclase-Activating Proteins†." Biochemistry 45, no. 6 (February 2006): 1899–909. http://dx.doi.org/10.1021/bi0519396.

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21

Ames, James B. "Structural Insights into Retinal Guanylate Cyclase Activator Proteins (GCAPs)." International Journal of Molecular Sciences 22, no. 16 (August 13, 2021): 8731. http://dx.doi.org/10.3390/ijms22168731.

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Retinal guanylate cyclases (RetGCs) promote the Ca2+-dependent synthesis of cGMP that coordinates the recovery phase of visual phototransduction in retinal rods and cones. The Ca2+-sensitive activation of RetGCs is controlled by a family of photoreceptor Ca2+ binding proteins known as guanylate cyclase activator proteins (GCAPs). The Mg2+-bound/Ca2+-free GCAPs bind to RetGCs and activate cGMP synthesis (cyclase activity) at low cytosolic Ca2+ levels in light-activated photoreceptors. By contrast, Ca2+-bound GCAPs bind to RetGCs and inactivate cyclase activity at high cytosolic Ca2+ levels found in dark-adapted photoreceptors. Mutations in both RetGCs and GCAPs that disrupt the Ca2+-dependent cyclase activity are genetically linked to various retinal diseases known as cone-rod dystrophies. In this review, I will provide an overview of the known atomic-level structures of various GCAP proteins to understand how protein dimerization and Ca2+-dependent conformational changes in GCAPs control the cyclase activity of RetGCs. This review will also summarize recent structural studies on a GCAP homolog from zebrafish (GCAP5) that binds to Fe2+ and may serve as a Fe2+ sensor in photoreceptors. The GCAP structures reveal an exposed hydrophobic surface that controls both GCAP1 dimerization and RetGC binding. This exposed site could be targeted by therapeutics designed to inhibit the GCAP1 disease mutants, which may serve to mitigate the onset of retinal cone-rod dystrophies.

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22

Hallett, M. A., J. L. Delaat, K. Arikawa, C. L. Schlamp, F. Kong, and D. S. Williams. "Distribution of guanylate cyclase within photoreceptor outer segments." Journal of Cell Science 109, no. 7 (July 1, 1996): 1803–12. http://dx.doi.org/10.1242/jcs.109.7.1803.

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Guanylate cyclases play an essential role in the recovery of vertebrate photoreceptor cells after light activation. Here, we have investigated how one such guanylate cyclase, RetGC-1, is distributed within light- and dark-adapted rod photoreceptor cells. Guanylate cyclase activity partitioned with the photoreceptor outer segment (OS) cytoskeleton in a light-sensitive manner. RetGC-1 was found to bind actin filaments in actin blot overlays, suggesting a mechanism for its association with the OS cytoskeleton. In retinal sections, this enzyme was immunodetected only in the OSs, where it appeared to be distributed throughout the disk membranes.

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23

Oliveira, Luanne, Pierre Miniou, Evani Viegas-Pequignot, Jean-Michel Rozet, Hélène Dollfus, and Steven J. Pittler. "Human Retinal Guanylate Cyclase (GUC2D) Maps to Chromosome 17p13.1." Genomics 22, no. 2 (July 1994): 478–81. http://dx.doi.org/10.1006/geno.1994.1415.

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Li, Ning, Robert N. Fariss, Kai Zhang, Annie Otto-Bruc, Francoise Haeseleer, Darin Bronson, Ning Qin, et al. "Guanylate-cyclase-inhibitory protein is a frog retinal Ca2+-binding protein related to mammalian guanylate-cyclase-activating proteins." European Journal of Biochemistry 252, no. 3 (March 15, 1998): 591–99. http://dx.doi.org/10.1046/j.1432-1327.1998.2520591.x.

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MARGULIS, ALEXANDER, NIKOLAY POZDNYAKOV, LOAN DANG, and ARI SITARAMAYYA. "Soluble guanylate cyclase and nitric oxide synthase in synaptosomal fractions of bovine retina." Visual Neuroscience 15, no. 5 (May 1998): 867–73. http://dx.doi.org/10.1017/s0952523898155098.

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Cyclic GMP has been shown in recent years to directly activate ion channels in bipolar and ganglion cells, and to indirectly regulate coupling between horizontal cells, and between bipolar and amacrine cells. In all of these cases, the effects of cyclic GMP are mimicked by nitric oxide. An increase in calcium concentration stimulates the production of nitric oxide by neuronal and endothelial forms of nitric oxide synthase, which in turn activates soluble guanylate cyclases, enhancing the synthesis of cyclic GMP. Though some effects of nitric oxide do not involve cyclic GMP, the nitric oxide-cyclic GMP cascade is well recognized as a signaling mechanism in brain and other tissues. The widespread occurrence of nitric oxide/cyclic GMP-regulated ion channel activity in retinal neurons raises the possibility that nitric-oxide-sensitive soluble guanylate cyclases play an important role in cell–cell communication, and possibly, synaptic transmission. Immunohistochemical studies have indicated the presence of soluble guanylate cyclase in retinal synaptic layers, but such studies are not suitable for determination of the density or quantitative subcellular distribution of the enzyme. Microanalytical methods involving microdissection of frozen retina also showed the presence of cyclase activity in retinal plexiform layers but these methods did not permit distinction between nitric oxide-sensitive and insensitive cyclases. In this study, we fractionated retinal homogenate into the cytosolic and synaptosomal fractions and investigated the specific activity and distribution of soluble guanylate cyclase and nitric oxide synthase. The results show that both enzymes are present in the synaptosomal fractions derived from inner and outer plexiform layers. The synaptosomal fraction derived from inner retina was highly enriched in cyclase activity. Nitric oxide synthase activity was also higher in the inner than outer retinal synaptosomal fraction. The results suggest that the nitric oxide-cyclic GMP system is operational in both synaptic layers of retina and that it may play a more significant role in the inner retina.

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Perrault, Isabella, Jean Michel Rozet, Patrick Calvas, Sylvie Gerber, Agnès Camuzat, Hélène Dollfus, Sophie Châtelin, et al. "Retinal–specific guanylate cyclase gene mutations in Leber's congenital amaurosis." Nature Genetics 14, no. 4 (December 1996): 461–64. http://dx.doi.org/10.1038/ng1296-461.

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Dizhoor, A., S. Ray, S. Kumar, G. Niemi, M. Spencer, D. Brolley, K. Walsh, P. Philipov, J. Hurley, and L. Stryer. "Recoverin: a calcium sensitive activator of retinal rod guanylate cyclase." Science 251, no. 4996 (February 22, 1991): 915–18. http://dx.doi.org/10.1126/science.1672047.

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Lim, Sunghyuk, Igor V. Peshenko, Alexander M. Dizhoor, and James B. Ames. "Structural Insights for Activation of Retinal Guanylate Cyclase by GCAP1." PLoS ONE 8, no. 11 (November 13, 2013): e81822. http://dx.doi.org/10.1371/journal.pone.0081822.

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Holden, Joseph M., Sara Al Hussein Al Awamlh, Louis-Philippe Croteau, Andrew M. Boal, Tonia S. Rex, Michael L. Risner, David J. Calkins, and Lauren K. Wareham. "Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice." International Journal of Molecular Sciences 23, no. 6 (March 12, 2022): 3066. http://dx.doi.org/10.3390/ijms23063066.

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The nitric oxide–guanylyl cyclase-1–cyclic guanylate monophosphate (NO–GC-1–cGMP) pathway is integral to the control of vascular tone and morphology. Mice lacking the alpha catalytic domain of guanylate cyclase (GC1−/−) develop retinal ganglion cell (RGC) degeneration with age, with only modest fluctuations in intraocular pressure (IOP). Increasing the bioavailability of cGMP in GC1−/− mice prevents neurodegeneration independently of IOP, suggesting alternative mechanisms of retinal neurodegeneration. In continuation to these studies, we explored the hypothesis that dysfunctional cGMP signaling leads to changes in the neurovascular unit that may contribute to RGC degeneration. We assessed retinal vasculature and astrocyte morphology in young and aged GC1−/− and wild type mice. GC1−/− mice exhibit increased peripheral retinal vessel dilation and shorter retinal vessel branching with increasing age compared to Wt mice. Astrocyte cell morphology is aberrant, and glial fibrillary acidic protein (GFAP) density is increased in young and aged GC1−/− mice, with areas of dense astrocyte matting around blood vessels. Our results suggest that proper cGMP signaling is essential to retinal vessel morphology with increasing age. Vascular changed are preceded by alterations in astrocyte morphology which may together contribute to retinal neurodegeneration and loss of visual acuity observed in GC1−/− mice.

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Shiells, Richard, and Gertrude Falk. "Retinal on-bipolar cells contain a nitric oxide-sensitive guanylate cyclase." NeuroReport 3, no. 10 (October 1992): 845–48. http://dx.doi.org/10.1097/00001756-199210000-00006.

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31

Koutalos, Y. "Characterization of guanylate cyclase activity in single retinal rod outer segments." Journal of General Physiology 106, no. 5 (November 1, 1995): 863–90. http://dx.doi.org/10.1085/jgp.106.5.863.

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32

Yamazaki, Matsuyo, Jiro Usukura, Russell K. Yamazaki, and Akio Yamazaki. "ATP binding is required for physiological activation of retinal guanylate cyclase." Biochemical and Biophysical Research Communications 338, no. 2 (December 2005): 1291–98. http://dx.doi.org/10.1016/j.bbrc.2005.10.087.

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Liu, Xinran, Keiji Seno, Yuji Nishizawa, Fumio Hayashi, Akio Yamazaki, Hiroyuki Matsumoto, Takashi Wakabayashi, and Jiro Usukura. "Ultrastructural localization of retinal guanylate cyclase in human and monkey retinas." Experimental Eye Research 59, no. 6 (December 1994): 761–68. http://dx.doi.org/10.1006/exer.1994.1162.

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34

Zulliger, Rahel, Muna I. Naash, Raju V. S. Rajala, Robert S. Molday, and Seifollah Azadi. "Impaired Association of Retinal Degeneration-3 with Guanylate Cyclase-1 and Guanylate Cyclase-activating Protein-1 Leads to Leber Congenital Amaurosis-1." Journal of Biological Chemistry 290, no. 6 (December 4, 2014): 3488–99. http://dx.doi.org/10.1074/jbc.m114.616656.

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35

Koch, Karl-Wilhelm, and Lubert Stryer. "Highly cooperative feedback control of retinal rod guanylate cyclase by calcium ions." Nature 334, no. 6177 (July 1988): 64–66. http://dx.doi.org/10.1038/334064a0.

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36

Horio, Yoshiyuki, and Ferid Murad. "Characterization and purification of retinal guanylate cyclase from bovine rod outer segments." Japanese Journal of Pharmacology 55 (1991): 222. http://dx.doi.org/10.1016/s0021-5198(19)38674-3.

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Margulis, A., R. M. Goraczniak, T. Duda, R. K. Sharma, and A. Sitaramayya. "Structural and Biochemical Identity of Retinal Rod Outer Segment Membrane Guanylate Cyclase." Biochemical and Biophysical Research Communications 194, no. 2 (July 1993): 855–61. http://dx.doi.org/10.1006/bbrc.1993.1900.

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38

Gorczyca, W. A., M. P. Gray-Keller, P. B. Detwiler, and K. Palczewski. "Purification and physiological evaluation of a guanylate cyclase activating protein from retinal rods." Proceedings of the National Academy of Sciences 91, no. 9 (April 26, 1994): 4014–18. http://dx.doi.org/10.1073/pnas.91.9.4014.

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39

Imanishi, Yoshikazu, Ning Li, Izabela Sokal, Mathew E. Sowa, Olivier Lichtarge, Theodore G. Wensel, David A. Saperstein, Wolfgang Baehr, and Krzysztof Palczewski. "Characterization of retinal guanylate cyclase-activating protein 3 (GCAP3) from zebrafish to man." European Journal of Neuroscience 15, no. 1 (January 2002): 63–78. http://dx.doi.org/10.1046/j.0953-816x.2001.01835.x.

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Pozdnyakov, Nikolay, Akiko Yoshida, Nigel G. F. Cooper, Alexander Margulis, Teresa Duda, Rameshwar K. Sharma, and Ari Sitaramayya. "A novel calcium-dependent activator of retinal rod outer segment membrane guanylate cyclase." Biochemistry 34, no. 44 (November 1995): 14279–83. http://dx.doi.org/10.1021/bi00044a002.

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41

Bonì, Francesco, Valerio Marino, Carlo Bidoia, Eloise Mastrangelo, Alberto Barbiroli, Daniele Dell’Orco, and Mario Milani. "Modulation of Guanylate Cyclase Activating Protein 1 (GCAP1) Dimeric Assembly by Ca2+ or Mg2+: Hints to Understand Protein Activity." Biomolecules 10, no. 10 (October 5, 2020): 1408. http://dx.doi.org/10.3390/biom10101408.

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The guanylyl cyclase-activating protein 1, GCAP1, activates or inhibits retinal guanylyl cyclase (retGC) depending on cellular Ca2+ concentrations. Several point mutations of GCAP1 have been associated with impaired calcium sensitivity that eventually triggers progressive retinal degeneration. In this work, we demonstrate that the recombinant human protein presents a highly dynamic monomer-dimer equilibrium, whose dissociation constant is influenced by salt concentration and, more importantly, by protein binding to Ca2+ or Mg2+. Based on small-angle X-ray scattering data, protein-protein docking, and molecular dynamics simulations we propose two novel three-dimensional models of Ca2+-bound GCAP1 dimer. The different propensity of human GCAP1 to dimerize suggests structural differences induced by cation binding potentially involved in the regulation of retGC activity.

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42

Miller, J. L., and J. I. Korenbrot. "In retinal cones, membrane depolarization in darkness activates the cGMP-dependent conductance. A model of Ca homeostasis and the regulation of guanylate cyclase." Journal of General Physiology 101, no. 6 (June 1, 1993): 933–60. http://dx.doi.org/10.1085/jgp.101.6.933.

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We measured outer segment currents under voltage clamp in solitary, single cone photoreceptors isolated from the retina of striped bass. In darkness, changes in membrane voltage to values more positive than 10 mV activate a time- and voltage-dependent outward current in the outer segment. This dark, voltage-activated current (DVAC) increases in amplitude with a sigmoidal time course up to a steady-state value, reached in 0.75-1.5 s. DVAC is entirely suppressed by light, and its current-voltage characteristics and reversal potential are the same as those of the light-sensitive currents. DVAC, therefore, arises from the activation by voltage in the dark of the light-sensitive, cGMP-gated channels of the cone outer segment. Since these channels are not directly gated by voltage, we explain DVAC as arising from a voltage-dependent decrease in cytoplasmic Ca concentration that, in turn, activates only guanylate cyclase and results in net synthesis of cGMP. This explanation is supported by the finding that the Ca buffer BAPTA, loaded into the cytoplasm of the cone outer segment, blocks DVAC. To link a decrease in cytoplasmic Ca concentration to the synthesis of cGMP and the characteristics of DVAC, we develop a quantitative model that assumes cytoplasmic Ca concentration can be continuously calculated from the balance between passive Ca influx via the cGMP-gated channel and its active efflux via a Na/Ca,K exchanger, and that further assumes that guanylate cyclase is activated by decreasing cytoplasmic Ca concentration with characteristics identical to those described for the enzyme in rods. The model successfully simulates experimental data by adjusting the Ca conductance of the cGMP-gated channels as a function of voltage and the Ca buffering power of the cytoplasm. This success suggests that the activity of guanylate cyclase in cone outer segments is indistinguishable from that in rods.

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Coccia, V. J., and R. H. Cote. "Regulation of intracellular cyclic GMP concentration by light and calcium in electropermeabilized rod photoreceptors." Journal of General Physiology 103, no. 1 (January 1, 1994): 67–86. http://dx.doi.org/10.1085/jgp.103.1.67.

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This study examines the regulation of cGMP by illumination and by calcium during signal transduction in vertebrate retinal photoreceptor cells. We employed an electropermeabilized rod outer segment (EP-ROS) preparation which permits perfusion of low molecular weight compounds into the cytosol while retaining many of the features of physiologically competent, intact rod outer segments (ROS). When nucleotide-depleted EP-ROS were incubated with MgGTP, time- and dose-dependent increases in intracellular cGMP levels were observed. The steady state cGMP concentration in EP-ROS (0.007 mol cGMP per mol rhodopsin) approached the cGMP concentration in intact ROS. Flash illumination of EP-ROS in a 250-nM free calcium medium resulted in a transient decrease in cGMP levels; this occurred in the absence of changes in calcium concentration. The kinetics of the cGMP response to flash illumination of EP-ROS were similar to that of intact ROS. To further examine the effects of calcium on cGMP metabolism, dark-adapted EP-ROS were incubated with MgGTP containing various concentrations of calcium. We observed a twofold increase in cGMP steady state levels as the free calcium was lowered from 1 microM to 20 nM; this increase was comparable to the behavior of intact ROS. Measurements of guanylate cyclase activity in EP-ROS showed a 3.5-fold increase in activity over this range of calcium concentrations, indicating a retention of calcium regulation of guanylate cyclase in EP-ROS preparations. Flash illumination of EP-ROS in either a 50- or 250-nM free calcium medium revealed a slowing of the recovery time course at the lower calcium concentration. This observation conflicts with any hypothesis whereby a reduction in free calcium concentration hastens the recovery of cytoplasmic cGMP levels, either by stimulating guanylate cyclase activity or by inhibiting phosphodiesterase activity. We conclude that changes in the intracellular calcium concentration during visual transduction may have more complex effects on the recovery of the photoresponse than can be accounted for solely by guanylate cyclase activation.

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Dell’Orco, Daniele, Petra Behnen, Sara Linse, and Karl-Wilhelm Koch. "Calcium binding, structural stability and guanylate cyclase activation in GCAP1 variants associated with human cone dystrophy." Cellular and Molecular Life Sciences 67, no. 6 (January 7, 2010): 973–84. http://dx.doi.org/10.1007/s00018-009-0243-8.

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45

Semple-Rowland, S. L., N. R. Lee, J. P. Van Hooser, K. Palczewski, and W. Baehr. "A null mutation in the photoreceptor guanylate cyclase gene causes the retinal degeneration chicken phenotype." Proceedings of the National Academy of Sciences 95, no. 3 (February 3, 1998): 1271–76. http://dx.doi.org/10.1073/pnas.95.3.1271.

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46

Koch, K. W., F. Eckstein, and L. Stryer. "Stereochemical course of the reaction catalyzed by guanylate cyclase from bovine retinal rod outer segments." Journal of Biological Chemistry 265, no. 17 (June 1990): 9659–63. http://dx.doi.org/10.1016/s0021-9258(19)38720-4.

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47

Rosenzweig, Derek H., K. Saidas Nair, Konstantin Levay, Igor V. Peshenko, John W. Crabb, Alexander M. Dizhoor, and Vladlen Z. Slepak. "Interaction of retinal guanylate cyclase with the α subunit of transducin: potential role in transducin localization." Biochemical Journal 417, no. 3 (January 16, 2009): 803–12. http://dx.doi.org/10.1042/bj20081513.

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Vertebrate phototransduction is mediated by cGMP, which is generated by retGC (retinal guanylate cyclase) and degraded by cGMP phosphodiesterase. Light stimulates cGMP hydrolysis via the G-protein transducin, which directly binds to and activates phosphodiesterase. Bright light also causes relocalization of transducin from the OS (outer segments) of the rod cells to the inner compartments. In the present study, we show experimental evidence for a previously unknown interaction between Gαt (the transducin α subunit) and retGC. Gαt co-immunoprecipitates with retGC from the retina or from co-transfected COS-7 cells. The retGC–Gαt complex is also present in cones. The interaction also occurs in mice lacking RGS9 (regulator of G-protein signalling 9), a protein previously shown to associate with both Gαt and retGC. The Gαt–retGC interaction is mediated primarily by the kinase homology domain of retGC, which binds GDP-bound Gαt stronger than the GTP[S] (GTPγS; guanosine 5′-[γ-thio]triphosphate) form. Neither Gαt nor Gβγ affect retGC-mediated cGMP synthesis, regardless of the presence of GCAP (guanylate cyclase activating protein) and Ca2+. The rate of light-dependent transducin redistribution from the OS to the inner segments is markedly accelerated in the retGC-1-knockout mice, while the migration of transducin to the OS after the onset of darkness is delayed. Supplementation of permeabilized photoreceptors with cGMP does not affect transducin translocation. Taken together, these results suggest that the protein–protein interaction between Gαt and retGC represents a novel mechanism regulating light-dependent translocation of transducin in rod photoreceptors.

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48

Shahu, Manisha Kumari, Fabian Schuhmann, Alexander Scholten, Ilia A. Solov’yov, and Karl-Wilhelm Koch. "The Transition of Photoreceptor Guanylate Cyclase Type 1 to the Active State." International Journal of Molecular Sciences 23, no. 7 (April 5, 2022): 4030. http://dx.doi.org/10.3390/ijms23074030.

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Membrane-bound guanylate cyclases (GCs), which synthesize the second messenger guanosine-3′, 5′-cyclic monophosphate, differ in their activation modes to reach the active state. Hormone peptides bind to the extracellular domain in hormone-receptor-type GCs and trigger a conformational change in the intracellular, cytoplasmic part of the enzyme. Sensory GCs that are present in rod and cone photoreceptor cells have intracellular binding sites for regulatory Ca2+-sensor proteins, named guanylate-cyclase-activating proteins. A rotation model of activation involving an α-helix rotation was described as a common activation motif among hormone-receptor GCs. We tested whether the photoreceptor GC-E underwent an α-helix rotation when reaching the active state. We experimentally simulated such a transitory switch by integrating alanine residues close to the transmembrane region, and compared the effects of alanine integration with the point mutation V902L in GC-E. The V902L mutation is found in patients suffering from retinal cone–rod dystrophies, and leads to a constitutively active state of GC-E. We analyzed the enzymatic catalytic parameters of wild-type and mutant GC-E. Our data showed no involvement of an α-helix rotation when reaching the active state, indicating a difference in hormone receptor GCs. To characterize the protein conformations that represent the transition to the active state, we investigated the protein dynamics by using a computational approach based on all-atom molecular dynamics simulations. We detected a swinging movement of the dimerization domain in the V902L mutant as the critical conformational switch in the cyclase going from the low to high activity state.

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Lim, Sunghyuk, Alexander Scholten, Grace Manchala, Diana Cudia, Sarah-Karina Zlomke-Sell, Karl-W. Koch, and James B. Ames. "Structural Characterization of Ferrous Ion Binding to Retinal Guanylate Cyclase Activator Protein 5 from Zebrafish Photoreceptors." Biochemistry 56, no. 51 (December 7, 2017): 6652–61. http://dx.doi.org/10.1021/acs.biochem.7b01029.

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50

Pozdnyakov, Nikolay, Alexander Margulis, and Ari Sitaramayya. "Identification of Effector Binding Sites on S100β: Studies with Guanylate Cyclase and p80, a Retinal Phosphoprotein†." Biochemistry 37, no. 30 (July 1998): 10701–8. http://dx.doi.org/10.1021/bi9802115.

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