Conformational analysis of the carboxy-terminal tails of human beta-tubulin isotypes.
Several isotypes of the structural protein tubulin have been characterized. Their expression offers a plausible explanation for differences regarding microtubule function. Although 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 examined the global conformational differences within a set of nine human beta-tubulin isotypes using replica exchange molecular dynamics simulations. Through the analysis of the resulting configuration ensembles, we quantified differences such as the CTTs sequence influence on overall flexibility and average secondary structure. Although 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.
Luchko
Tyler
T
Department of Physics, University of Alberta, Edmonton, Alberta T6G 2G7, Canada.
Huzil
J Torin
JT
Stepanova
Maria
M
Tuszynski
Jack
J
D000465:Algorithms; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D003201:Computers; D018360:Crystallography, X-Ray / Q000379:methods; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry; D025341:Principal Component Analysis; D011487:Protein Conformation; D020033:Protein Isoforms; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014404:Tubulin / Q000737:chemistry*
D010455:Peptides; D020033:Protein Isoforms; D014404:Tubulin