5h3n
From Proteopedia
Solution structure of human Gelsolin protein domain 1 at pH 7.3
Structural highlights
DiseaseGELS_HUMAN Defects in GSN are the cause of amyloidosis type 5 (AMYL5) [MIM:105120; also known as familial amyloidosis Finnish type. AMYL5 is a hereditary generalized amyloidosis due to gelsolin amyloid deposition. It is typically characterized by cranial neuropathy and lattice corneal dystrophy. Most patients have modest involvement of internal organs, but severe systemic disease can develop in some individuals causing peripheral polyneuropathy, amyloid cardiomyopathy, and nephrotic syndrome leading to renal failure.[1] [2] [3] [4] FunctionGELS_HUMAN Calcium-regulated, actin-modulating protein that binds to the plus (or barbed) ends of actin monomers or filaments, preventing monomer exchange (end-blocking or capping). It can promote the assembly of monomers into filaments (nucleation) as well as sever filaments already formed. Plays a role in ciliogenesis.[5] Publication Abstract from PubMedSix-domain gelsolin regulates actin structural dynamics through its abilities to sever, cap and uncap F-actin. These activities are modulated by various cellular parameters like Ca(2+) and pH. Until now, only the molecular activation mechanism of gelsolin by Ca(2+) has been understood relatively well. The fragment comprising the first domain and six residues from the linker region into the second domain has been shown to be similar to the full-length protein in F-actin severing activity in the absence of Ca(2+) at pH 5. To understand how this gelsolin fragment is activated for F-actin severing by lowering pH, we solved its NMR structures at both pH 7.3 and 5 in the absence of Ca(2+) and measured the pKa values of acidic amino acid residues and histidine residues. The overall structure and dynamics of the fragment are not affected significantly by pH. Nevertheless, local structural changes caused by protonation of His29 and Asp109 result in the activation on lowering the pH, and protonation of His151 directly effects filament binding since it resides in the gelsolin/actin interface. Mutagenesis studies support that His29, Asp109 and His151 play important roles in the pH-dependent severing activity of the gelsolin fragment. Structural Basis for pH-mediated Regulation of F-actin Severing by Gelsolin Domain 1.,Fan JS, Goh H, Ding K, Xue B, Robinson RC, Yang D Sci Rep. 2017 Mar 28;7:45230. doi: 10.1038/srep45230. PMID:28349924[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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