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PMID: 17134719 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Self-masking in an intact ERM-merlin protein: an active role for the central alpha-helical domain.

Journal of molecular biology ·Vol. 365 ·No. 5 ·2007-02-02 ·Pages 1446-59

Li Q, Nance MR, Kulikauskas R, Nyberg K, Fehon R, Karplus PA, Bretscher A, Tesmer JJ

Abstract

Ezrin/radixin/moesin (ERM) family members provide a regulated link between the cortical actin cytoskeleton and the plasma membrane to govern membrane structure and organization. Here, we report the crystal structure of intact insect moesin, revealing that its essential yet previously uncharacterized alpha-helical domain forms extensive interactions with conserved surfaces of the band four-point-one/ezrin/radixin/moesin (FERM) domain. These interdomain contacts provide a functional explanation for how PIP(2) binding and tyrosine phosphorylation of ezrin lead to activation, and provide an understanding of previously enigmatic loss-of-function missense mutations in the tumor suppressor merlin. Sequence conservation and biochemical results indicate that this structure represents a complete model for the closed state of all ERM-merlin proteins, wherein the central alpha-helical domain is an active participant in an extensive set of inhibitory interactions that can be unmasked, in a rheostat-like manner, by coincident regulatory factors that help determine cell polarity and membrane structure.

MeSH Terms
Amino Acid Sequence Animals Binding Sites Conserved Sequence Crystallography, X-Ray Cytoskeletal Proteins/chemistry Humans Membrane Proteins/chemistry Microfilament Proteins/chemistry,metabolism Models, Molecular Molecular Sequence Data Neurofibromin 2/chemistry Protein Binding Protein Structure, Secondary Protein Structure, Tertiary Spodoptera/metabolism Structural Homology, Protein Structure-Activity Relationship
Chemicals
Cytoskeletal Proteins Membrane Proteins Microfilament Proteins Neurofibromin 2 ezrin moesin radixin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Li Qianzhi
Department of Chemistry and Biochemistry, Institute for Cellular and Molecular Biology, The University of Texas at Austin 1 University Station #A5300, Austin, TX 78712-0165, USA.
Nance Mark R
Kulikauskas Rima
Nyberg Kevin
Fehon Richard
Karplus P Andrew
Bretscher Anthony
Tesmer John J G
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Article Info
Journal
Journal of molecular biology
Abbr.
J Mol Biol
ISSN
0022-2836
DOI
10.1016/j.jmb.2006.10.075
Published
2007-02-02
Epub
2006-00-26
Pages
1446-59
Language
English
Region
England
NLM ID
2985088R
PMCID
PMC1796844
Subset
IM
Grants
NINDS NIH HHS · R01 NS034783-12 · United States
NIGMS NIH HHS · R01 GM036652 · United States
NHLBI NIH HHS · HL 071818 · United States
NIGMS NIH HHS · GM 36652 · United States
NINDS NIH HHS · R56 NS034783 · United States
NINDS NIH HHS · R01 NS034783 · United States
NHLBI NIH HHS · R01 HL071818 · United States
NINDS NIH HHS · NS 034783 · United States
Databases
GENBANK
EF071985
PDB
2I1J, 2I1K
External Links
PubMed source DOI: 10.1016/j.jmb.2006.10.075 PMC Full Text View journal details
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