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Title: Encephalomyocarditis virus Leader protein hinge domain is responsible for interactions with Ran GTPase

Encephalomyocarditis virus (EMCV), a Cardiovirus, initiates its polyprotein with a short 67 amino acid Leader (L) sequence. The protein acts as a unique pathogenicity factor, with anti-host activities which include the triggering of nuclear pore complex hyperphosphorylation and direct binding inhibition of the active cellular transport protein, Ran GTPase. Chemical modifications and protein mutagenesis now map the Ran binding domain to the L hinge-linker region, and in particular, to amino acids 35–40. Large deletions affecting this region were shown previously to diminish Ran binding. New point mutations, especially K35Q, D37A and W40A, preserve the intact L structure, abolish Ran binding and are deficient for nucleoporin (Nup) hyperphosphorylation. Ran itself morphs through multiple configurations, but reacts most effectively with L when in the GDP format, preferably with an empty nucleotide binding pocket. Therefore, L:Ran binding, mediated by the linker-hinge, is a required step in L-induced nuclear transport inhibition. - Highlights: • The hinge domain provides critical residues in Cardiovirus L:Ran complex formation. • Leader prefers to bind Ran in a nucleotide free, GDP-conformation. • L-induced Nup62 phosphorylation is reduced with Ran-deficient binding mutations.
Authors:
 [1] ;  [1] ;  [2]
  1. Institute for Molecular Virology, University of Wisconsin-Madison, R.M. Bock Laboratories, 1525 Linden Dr. Madison, WI 53706 (United States)
  2. (United States)
Publication Date:
OSTI Identifier:
22436631
Resource Type:
Journal Article
Resource Relation:
Journal Name: Virology; Journal Volume: 443; Journal Issue: 1; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AMINO ACIDS; GENE MUTATIONS; INHIBITION; MUTAGENESIS; NEM; PHOSPHATES; PHOSPHORYLATION; PROTEINS; RESIDUES; VIRUSES