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Title: The Dc-Module of Doublecortin: Dynamics, Domain Boundaries, and Functional Implications

Abstract

The doublecortin-like (DC) domains, which usually occur in tandem, constitute novel microtubule-binding modules. They were first identified in doublecortin (DCX), a protein expressed in migrating neurons, and in the doublecortin-like kinase (DCLK). They are also found in other proteins, including the RP1 gene product which-when mutated-causes a form of inherited blindness. We previously reported an X-ray structure of the N-terminal DC domain of DCLK (N-DCLK), and a solution structure of an analogous module of human doublecortin (N-DCX). These studies showed that the DC domain has a tertiary fold closely reminiscent of ubiquitin and similar to several GTPase-binding domains. We now report an X-ray structure of a mutant of N-DCX, in which the C-terminal fragment (residues 139-147) unexpectedly shows an altered, 'open' conformation. However, heteronuclear NMR data show that this C-terminal fragment is only transiently open in solution, and assumes a predominantly 'closed' conformation. While the 'open' conformation may be artificially stabilized by crystal packing interactions, the observed switching between the 'open' and 'closed' conformations, which shortens the linker between the two DC-domains by {approx}20 A, is likely to be of functional importance in the control of tubulin polymerization and microtubule bundling by doublecortin.

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930656
Report Number(s):
BNL-81133-2008-JA
TRN: US200901%%167
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proteins: Structure, Functions, and Bioinformatics; Journal Volume: 64
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; FUNCTIONALS; GENES; MICROTUBULES; MUTANTS; NERVE CELLS; PHOSPHOTRANSFERASES; POLYMERIZATION; PROTEINS; RESIDUES; national synchrotron light source

Citation Formats

Cierpicki,T., Kim, M., Cooper, D., Derewenda, U., Bushweller, J., and Derwenda, Z.. The Dc-Module of Doublecortin: Dynamics, Domain Boundaries, and Functional Implications. United States: N. p., 2007. Web.
Cierpicki,T., Kim, M., Cooper, D., Derewenda, U., Bushweller, J., & Derwenda, Z.. The Dc-Module of Doublecortin: Dynamics, Domain Boundaries, and Functional Implications. United States.
Cierpicki,T., Kim, M., Cooper, D., Derewenda, U., Bushweller, J., and Derwenda, Z.. Mon . "The Dc-Module of Doublecortin: Dynamics, Domain Boundaries, and Functional Implications". United States. doi:.
@article{osti_930656,
title = {The Dc-Module of Doublecortin: Dynamics, Domain Boundaries, and Functional Implications},
author = {Cierpicki,T. and Kim, M. and Cooper, D. and Derewenda, U. and Bushweller, J. and Derwenda, Z.},
abstractNote = {The doublecortin-like (DC) domains, which usually occur in tandem, constitute novel microtubule-binding modules. They were first identified in doublecortin (DCX), a protein expressed in migrating neurons, and in the doublecortin-like kinase (DCLK). They are also found in other proteins, including the RP1 gene product which-when mutated-causes a form of inherited blindness. We previously reported an X-ray structure of the N-terminal DC domain of DCLK (N-DCLK), and a solution structure of an analogous module of human doublecortin (N-DCX). These studies showed that the DC domain has a tertiary fold closely reminiscent of ubiquitin and similar to several GTPase-binding domains. We now report an X-ray structure of a mutant of N-DCX, in which the C-terminal fragment (residues 139-147) unexpectedly shows an altered, 'open' conformation. However, heteronuclear NMR data show that this C-terminal fragment is only transiently open in solution, and assumes a predominantly 'closed' conformation. While the 'open' conformation may be artificially stabilized by crystal packing interactions, the observed switching between the 'open' and 'closed' conformations, which shortens the linker between the two DC-domains by {approx}20 A, is likely to be of functional importance in the control of tubulin polymerization and microtubule bundling by doublecortin.},
doi = {},
journal = {Proteins: Structure, Functions, and Bioinformatics},
number = ,
volume = 64,
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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