6cku

Publication Abstract from PubMed

The ancient and pluripotent progranulins contain multiple repeats of a cysteine-rich sequence motif of approximately 60 amino acids, called the granulin/epithelin module (GEM) with a prototypic structure of four beta-hairpins zipped together by six inter-hairpin disulfide bonds. Prevalence of this disulfide-enforced structure is assessed here by an expression screening of 19 unique GEM sequences of the four progranulins in the zebrafish genome, progranulins 1, 2, A and B. While a majority of the expressed GEM peptides did not exhibit uniquely-folded conformations, module AaE from progranulin A and AbB from progranulin B were found to fold into the protopypic 4-hairpin structure along with disulfide formation. Module AaE has the most-rigid three-dimensional structure with all four beta-hairpins defined using high-resolution (H-(15) N) NMR spectroscopy, including 492 inter-proton nuclear Overhauser effects, 23 (3) J(HN,Halpha ) coupling constants, 22 hydrogen bonds as well as residual dipolar coupling constants. Three-dimensional structure of AaE and the partially-folded AbB re-iterate the conformational stability of the N-terminal stack of two beta-hairpins and varying degrees of structural flexibility for the C-terminal half of the 4-hairpin global fold of the GEM repeat. A cell-based assay demonstrated a functional activity for the zebrafish granulin AaE in promoting the survival of neuronal cells, similarly to what has been found for the corresponding granulin E module in human progranulin. Finally, this work highlights the remaining challenges in structure-activity studies of proteins containing the GEM repeats, due to the apparent prevalence of structural disorder in GEM motifs despite potentially a high density of intramolecular disulfide bonds. This article is protected by copyright. All rights reserved.

Structure Dissection of Zebrafish Progranulins Identifies a Well-Folded Granulin/Epithelin Module Protein with pro-Cell Survival Activities.,Wang P, Chitramuthu B, Bateman A, Bennett HPJ, Xu P, Ni F Protein Sci. 2018 May 7. doi: 10.1002/pro.3441. PMID:29732682^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.