Molecular Mechanisms of Macular Degeneration Associated with the Complement Factor H Y402H Mutation

Abstract

A single nucleotide polymorphism, tyrosine at position 402 to histidine (Y402H), within the gene encoding complement factor H (FH) predisposes individuals to acquiring age-related macular degeneration (AMD) after aging. This polymorphism occurs in short consensus repeat (SCR) 7 of FH and results in decreased binding affinity of SCR6-8 for heparin. As FH is responsible for regulating the complement system, decreased affinity for heparin results in decreased regulation on surfaces of self. To understand the involvement of the Y402H polymorphism in AMD, we leverage methods from bioinformatics and computational biophysics to quantify structural and dynamical differences between SCR7 isoforms that contribute to decreased pattern recognition in SCR7 H402 . Our data from molecular and Brownian dynamics simulations suggest a revised mechanism for decreased heparin binding. In this model, transient contacts not observed in structures for SCR7 are predicted to occur in molecular dynamics simulations between coevolved residues Y402 and I412, stabilizing SCR7 Y402 in a conformation that promotes association with heparin. H402 in the risk isoform is less likely to form a contact with I412 and samples a larger conformational space than Y402. We observe energy minima for sidechains of Y402 and R404 from SCR7 Y402 that are predicted to associate with heparin at a rate constant faster than energy minima for sidechains of H402 and R404 from SCR7 H402 . As both carbohydrate density and degree of sulfation decrease with age in Bruch's membrane of the macula, the decreased heparin recognition of SCR7 H402 may contribute to the pathogenesis of AMD.

Complement family member CFI polymorphisms and AMD susceptibility from a comprehensive analysis

“…The associations among AMD development and these genes majority involves gene polymorphisms. The highest score of association was CFH (0.999), Harrison et al suggested the decreased heparin-binding affinity caused by the Y402H polymorphism (a common SNP in CFH gene) may recognize of SCR7 H402 , which may contribute to the pathogenesis of AMD [54]. C3 gene contains many SNPs, our previous meta and Zhang et al both detected some increased and decreased SNPs in AMD [19,55].…”

Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition

“…Electrostatic hotspot analysis has been performed using the AESOP (Analysis of Electrostatic Similarities Of Proteins) code, developed by Morikis ( Kieslich et al, 2011b ; Harrison et al, 2017 ) and extensively employed for electrostatic analysis of proteins ( Kieslich et al, 2011a , Kieslich et al, 2011b ; Gorham et al, 2011a , Gorham et al, 2011b ; Harrison et al, 2015 ; Mohan et al, 2015 , Mohan et al, 2016 ; Zewde et al, 2018 ; Harrison and Morikis, 2019 ). AESOP enables the analysis of electrostatic hotspots through the calculation of an Electrostatic Similarity Indices (ESI), ( Kieslich and Morikis, 2012 ), which assesses the electrostatic potential upon perturbation (i.e., mutagenesis), identifying regions of high electrostatic similarity, or those regions least affected by perturbation.…”

Polyelectrolytes for Enzyme Immobilization and the Regulation of Their Properties

“…It is noteworthy that computational approaches enable the testing of the effect of protein point mutations on its binding to a polyelectrolyte [ 95 , 96 ], providing a good opportunity for in silico estimation of the prospect of the modified enzyme immobilization. It might also be useful for studying the biological effects of post-translational modification, such as glycosylation [ 97 , 98 ] since cells contain many types of non-protein polyelectrolytes [ 99 ].…”