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Title: Structural Insights into the Interaction of the Evolutionarily Conserved ZPR1 Domain Tandem with Eukaryotic EF1A, Receptors, and SMN Complexes

Abstract

Eukaryotic genomes encode a zinc finger protein (ZPR1) with tandem ZPR1 domains. In response to growth stimuli, ZPR1 assembles into complexes with eukaryotic translation elongation factor 1A (eEF1A) and the survival motor neurons protein. To gain insight into the structural mechanisms underlying the essential function of ZPR1 in diverse organisms, we determined the crystal structure of a ZPR1 domain tandem and characterized the interaction with eEF1A. The ZPR1 domain consists of an elongation initiation factor 2-like zinc finger and a double-stranded {beta} helix with a helical hairpin insertion. ZPR1 binds preferentially to GDP-bound eEF1A but does not directly influence the kinetics of nucleotide exchange or GTP hydrolysis. However, ZPR1 efficiently displaces the exchange factor eEF1B from preformed nucleotide-free complexes, suggesting that it may function as a negative regulator of eEF1A activation. Structure-based mutational and complementation analyses reveal a conserved binding epitope for eEF1A that is required for normal cell growth, proliferation, and cell cycle progression. Structural differences between the ZPR1 domains contribute to the observed functional divergence and provide evidence for distinct modalities of interaction with eEF1A and survival motor neuron complexes.

Authors:
; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
929961
Report Number(s):
BNL-80565-2008-JA
TRN: US200822%%1125
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the USA; Journal Volume: 104; Journal Issue: 35
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; ANIMAL CELLS; CELL CYCLE; COMPLEXES; CRYSTAL STRUCTURE; ELONGATION; FINGERS; FUNCTIONS; GROWTH; HYDROLYSIS; INTERACTIONS; KINETICS; NERVE CELLS; NUCLEOTIDES; CELL PROLIFERATION; PROTEINS; RECEPTORS; STIMULI; ZINC; national synchrotron light source

Citation Formats

Mishra,A., Gangwani, L., Davis, R., and Lambright, D. Structural Insights into the Interaction of the Evolutionarily Conserved ZPR1 Domain Tandem with Eukaryotic EF1A, Receptors, and SMN Complexes. United States: N. p., 2007. Web. doi:10.1073/pnas.0704915104.
Mishra,A., Gangwani, L., Davis, R., & Lambright, D. Structural Insights into the Interaction of the Evolutionarily Conserved ZPR1 Domain Tandem with Eukaryotic EF1A, Receptors, and SMN Complexes. United States. doi:10.1073/pnas.0704915104.
Mishra,A., Gangwani, L., Davis, R., and Lambright, D. Mon . "Structural Insights into the Interaction of the Evolutionarily Conserved ZPR1 Domain Tandem with Eukaryotic EF1A, Receptors, and SMN Complexes". United States. doi:10.1073/pnas.0704915104.
@article{osti_929961,
title = {Structural Insights into the Interaction of the Evolutionarily Conserved ZPR1 Domain Tandem with Eukaryotic EF1A, Receptors, and SMN Complexes},
author = {Mishra,A. and Gangwani, L. and Davis, R. and Lambright, D.},
abstractNote = {Eukaryotic genomes encode a zinc finger protein (ZPR1) with tandem ZPR1 domains. In response to growth stimuli, ZPR1 assembles into complexes with eukaryotic translation elongation factor 1A (eEF1A) and the survival motor neurons protein. To gain insight into the structural mechanisms underlying the essential function of ZPR1 in diverse organisms, we determined the crystal structure of a ZPR1 domain tandem and characterized the interaction with eEF1A. The ZPR1 domain consists of an elongation initiation factor 2-like zinc finger and a double-stranded {beta} helix with a helical hairpin insertion. ZPR1 binds preferentially to GDP-bound eEF1A but does not directly influence the kinetics of nucleotide exchange or GTP hydrolysis. However, ZPR1 efficiently displaces the exchange factor eEF1B from preformed nucleotide-free complexes, suggesting that it may function as a negative regulator of eEF1A activation. Structure-based mutational and complementation analyses reveal a conserved binding epitope for eEF1A that is required for normal cell growth, proliferation, and cell cycle progression. Structural differences between the ZPR1 domains contribute to the observed functional divergence and provide evidence for distinct modalities of interaction with eEF1A and survival motor neuron complexes.},
doi = {10.1073/pnas.0704915104},
journal = {Proceedings of the National Academy of Sciences of the USA},
number = 35,
volume = 104,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}
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