Conformational Analysis of the Carboxy-Terminal Tails of Human -Tubulin Isotypes

¹ University of Alberta
² Cross Cancer Institue
³ NINT NRC
⁴ Cross Cancer Institute

^* To whom correspondence should be addressed. E-mail: jtus{at}phys.ualberta.ca.

Submitted on June 13, 2007
Revised on August 22, 2007
Accepted on 22 October 2007

	Abstract

Several isotypes of the structural protein tubulin have been characterized and their expression offers a plausible explanation for differences regarding microtubule function. While sequence variation between tubulin isotypes occurs throughout the entire protein, it is the extreme carboxy-terminal tails (CTTs) that exhibit the greatest concentration of differences. In humans, the CTTs range in length from 9 to 25 residues and because of a considerable number of glutamic acid residues, contain over 1/3 of tubulin's total electrostatic charge. The CTTs are believed to be highly disordered and their precise function has yet to be determined. However, their absence has been shown to result in altered microtubule stability and a reduction in the interaction with several microtubule -associated proteins (MAPs). To characterize the role that CTTs play in microtubule function, we have examined the global conformational differences within a set of nine human -tubulin isotypes using replica exchange molecular dynamics simulations. Through the analysis of the resulting configuration ensembles, we have quantified differences such as the CTTs sequence influence on overall flexibility and average secondary structure. While only minor variations between each CTT were observed, we suggest that these differences may be significant enough to affect interactions with MAPs, thereby influencing important properties, such as microtubule assembly and stability.

Key Words: C-termini, Tubulin,, cluster analysis, flexibility, principal component analysis, replica exchange molecular dynamics