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Title: Three-Dimensional Structure of Cofilin Bound to Monomeric Actin Derived by Structural Mass Spectrometry Data

Abstract

The cytoskeletal protein, actin, has its structure and function regulated by cofilin. In the absence of an atomic resolution structure for the actin/cofilin complex, the mechanism of cofilin regulation is poorly understood. Theoretical studies based on the similarities of cofilin and gelsolin segment 1 proposed the cleft between subdomains 1 and 3 in actin as the cofilin binding site. We used radiolytic protein footprinting with mass spectrometry and molecular modeling to provide an atomic model of how cofilin binds to monomeric actin. Footprinting data suggest that cofilin binds to the cleft between subdomains 1 and 2 in actin and that cofilin induces further closure of the actin nucleotide cleft. Site-specific fluorescence data confirm these results. The model identifies key ionic and hydrophobic interactions at the binding interface, including hydrogen-bonding between His-87 of actin to Ser-89 of cofilin that may control the charge dependence of cofilin binding. This model and its implications fill an especially important niche in the actin field, owing to the fact that ongoing crystallization efforts of the actin/cofilin complex have so far failed. This 3D binary complex structure is derived from a combination of solution footprinting data and computational approaches and outlines a general method for determiningmore » the structure of such complexes.« less

Authors:
; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959491
Report Number(s):
BNL-82477-2009-JA
Journal ID: ISSN 0027-8424; PNASA6; TRN: US1005747
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: 19
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 74 ATOMIC AND MOLECULAR PHYSICS; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; ACTIN; ATOMIC MODELS; CLOSURES; CRYSTALLIZATION; FLUORESCENCE; MASS SPECTROSCOPY; NUCLEOTIDES; PROTEINS; REGULATIONS; RESOLUTION; SIMULATION; national synchrotron light source

Citation Formats

Amisha Kamal,J., Benchaar, S., Takamoto, K., Reisler, E., and Chance, M. Three-Dimensional Structure of Cofilin Bound to Monomeric Actin Derived by Structural Mass Spectrometry Data. United States: N. p., 2007. Web. doi:10.1073/pnas.0611283104.
Amisha Kamal,J., Benchaar, S., Takamoto, K., Reisler, E., & Chance, M. Three-Dimensional Structure of Cofilin Bound to Monomeric Actin Derived by Structural Mass Spectrometry Data. United States. doi:10.1073/pnas.0611283104.
Amisha Kamal,J., Benchaar, S., Takamoto, K., Reisler, E., and Chance, M. Mon . "Three-Dimensional Structure of Cofilin Bound to Monomeric Actin Derived by Structural Mass Spectrometry Data". United States. doi:10.1073/pnas.0611283104.
@article{osti_959491,
title = {Three-Dimensional Structure of Cofilin Bound to Monomeric Actin Derived by Structural Mass Spectrometry Data},
author = {Amisha Kamal,J. and Benchaar, S. and Takamoto, K. and Reisler, E. and Chance, M.},
abstractNote = {The cytoskeletal protein, actin, has its structure and function regulated by cofilin. In the absence of an atomic resolution structure for the actin/cofilin complex, the mechanism of cofilin regulation is poorly understood. Theoretical studies based on the similarities of cofilin and gelsolin segment 1 proposed the cleft between subdomains 1 and 3 in actin as the cofilin binding site. We used radiolytic protein footprinting with mass spectrometry and molecular modeling to provide an atomic model of how cofilin binds to monomeric actin. Footprinting data suggest that cofilin binds to the cleft between subdomains 1 and 2 in actin and that cofilin induces further closure of the actin nucleotide cleft. Site-specific fluorescence data confirm these results. The model identifies key ionic and hydrophobic interactions at the binding interface, including hydrogen-bonding between His-87 of actin to Ser-89 of cofilin that may control the charge dependence of cofilin binding. This model and its implications fill an especially important niche in the actin field, owing to the fact that ongoing crystallization efforts of the actin/cofilin complex have so far failed. This 3D binary complex structure is derived from a combination of solution footprinting data and computational approaches and outlines a general method for determining the structure of such complexes.},
doi = {10.1073/pnas.0611283104},
journal = {Proceedings of the National Academy of Sciences of the USA},
number = 19,
volume = 104,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}