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Structural characterization of the LysR-type virulence factor, AphB, and insight into its mehcanism of transcriptional activation at the tcpPH promoter in Vibrio cholerae

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Call No.	QD47.5.N43 D3 2012tay
Author	Taylor, Jennifer Lynn.
Title	Structural characterization of the LysR-type virulence factor, AphB, and insight into its mehcanism of transcriptional activation at the tcpPH promoter in Vibrio cholerae
Date	2012
Abstract	The LysR-type virulence regulator, AphB, initiates the Vibrio cholerae virulence cascade resulting in expression of the two critical virulence factors, toxin-coregulated pilus and cholera toxin, by activating transcription at the tcpPH promoter. Several residues in the ligand-binding pocket of AphB influence its ability to respond to intracellular pH as well as to anaerobiosis. Substitution of five of these residues with negatively charged residues conferred constitutive activity to AphB under non-inducing pH conditions. The 2.2 � X-ray crystal structure of full-length AphB revealed that, like other LysR-type proteins, AphB is a tetramer with two distinct subunit conformations. Unlike other family members, AphB must undergo a significant conformational change in order to bind to DNA. To gain insight into the activation mechanism for AphB, the structure of one of the constitutive mutants, N100E AphB, was solved to 2.7 �. Comparison of the activated N100E protein structure with wild-type AphB reveals conformational changes that would allow DNA binding. Taken together, these results describe a pathway of structural rearrangements allowing communication between the ligand and DNA binding regions of AphB. Point mutations and exon deletions in the microtubule-severing ATPase, spastin, are responsible for approximately 40% of cases of autosomal dominant HSP, a motor neuron disease caused by a progressive degeneration of the motor axons of the corticospinal tract. Spastin is a member of the large family of AAA ATPases. These proteins serve diverse cellular functions and form hexameric ring structures in their active state. The X-ray crystal structure of a hydrolysis-deficient mutant (E442Q) of the human spastin protein AAA domain was solved with data to 3.3 � and analyzed in the context of the existing Drosophila melanogaster spastin AAA domain structure and crystal structures of other closely related proteins. Protein-protein contacts within the crystal lattice, which forms a six-fold spiral of spastin monomers, were compared to those observed in structures of AAA protein hexamers. This work has helped to build a more unifying framework for understanding the structural features of this group of microtubule-severing ATPases.
Description	xvii, 208 leaves : ill. (some col.) ; 28 cm.
Format	application/pdf
Advisor	Kull, F. Jon; Cantor, Robert S.; Wilcox, Dean E.; Momany, Cory
College	Dartmouth College -- Department of Chemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.432

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	Structural characterization of the LysR-type virulence factor, AphB, and insight into its mechanism of transcriptional activation at the tcpPH promoter in Vibrio cholerae A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry by Jennifer Lynn Taylor DARTMOUTH COLLEGE Hanover, New Hampshire May, 2012 Examining Committee: F. Jon Kull, Ph.D. (Chair) Robert S. Cantor, Ph.D. Dean E. Wilcox, Ph.D. Cory Momany, Ph.D. Brian W. Pogue, Ph.D. Dean of Graduate Studies

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Structural characterization of the LysR-type virulence factor, AphB, and insight into its mehcanism of transcriptional activation at the tcpPH promoter in Vibrio cholerae

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