The Molecular Organization of Human cGMP Specific Phosphodiesterase 6 (PDE6): Structural Implications of Somatic Mutations in Cancer and Retinitis Pigmentosa

Arooma Maryam,Sundeep Chaitanya Vedithi,Rana Rehan Khalid,Ali F Alsulami,Pedro Henrique Monteiro Torres,Abdul Rauf Siddiqi,Tom L Blundell

doi:10.1016/j.csbj.2019.03.004

Arooma Maryam, Sundeep Chaitanya Vedithi + Show 5 more

Open Access

https://doi.org/10.1016/j.csbj.2019.03.004

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Abstract

In the cyclic guanosine monophosphate (cGMP) signaling pathway, phosphodiesterase 6 (PDE6) maintains a critical balance of the intracellular concentration of cGMP by catalyzing it to 5′ guanosine monophosphate (5′-GMP). To gain insight into the mechanistic impacts of the PDE6 somatic mutations that are implicated in cancer and retinitis pigmentosa, we first defined the structure and organization of the human PDE6 heterodimer using computational comparative modelling. Each subunit of PDE6αβ possesses three domains connected through long α-helices. The heterodimer model indicates that the two chains are likely related by a pseudo two-fold axis. The N-terminal region of each subunit is comprised of two allosteric cGMP-binding domains (Gaf-A & Gaf-B), oriented in the same way and interacting with the catalytic domain present at the C-terminal in a way that would allow the allosteric cGMP-binding domains to influence catalytic activity. Subsequently, we applied an integrated knowledge-driven in silico mutation analysis approach to understand the structural and functional implications of experimentally identified mutations that cause various cancers and retinitis pigmentosa, as well as computational saturation mutagenesis of the dimer interface and cGMP-binding residues of both Gaf-A, and the catalytic domains. We studied the impact of mutations on the stability of PDE6αβ structure, subunit-interfaces and Gaf-cGMP interactions. Further, we discussed the changes in interatomic interactions of mutations that are destabilizing in Gaf-A (R93L, V141 M, F162 L), catalytic domain (D600N, F742 L, F776 L) and at the dimer interface (F426A, F248G, F424 N). This study establishes a possible link of change in PDE6αβ structural stability to the experimentally observed disease phenotypes.

Highlights

In living organisms, synchronized cellular communication among integrated signaling circuits is necessary to ensure proper cellular function
Chain A (PDE6α) of phosphodiesterase 6 (PDE6) encoded by PDE6A gene includes residues from positions 53–823 while chain B (PDE6β) encoded by PDE6B gene is comprised of 68–831 amino acids
Discussion and Conclusion cyclic guanosine monophosphate (cGMP)-specific phosphodiesterases regulate a myriad of cellular signaling processes through critical regulation of the cGMP messenger molecule and any disruption/dysregulation in the signaling pathways may lead to downstream pathophysiological impacts [2]

Summary

Introduction

In living organisms, synchronized cellular communication among integrated signaling circuits is necessary to ensure proper cellular function. Accurate signal transduction of extracellular cues to interior of the cells is coordinated between multiple compartmentalized intracellular signaling pathways through the recruitment of a distinct subset of sensing molecules [51,59]. 3000 signaling proteins and approximately 15 distinct second messenger molecules are known in mammals [24,35]. In the late 1980s, nitric oxide (NO) was discovered as the first diffusible primary signaling molecule that binds and activates soluble guanylate cyclase (sGC) to produce 3′, 5′cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). Cyclic guanosine monophosphate is a vital secondary messenger molecule that elicits (T.L. Blundell)

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