Emerging β-Sheet Rich Conformations in Supercompact Huntingtin Exon-1 Mutant Structures.

Autor:	Kang H; Computational Biology Center, IBM Thomas J. Watson Research Center , Yorktown Heights, New York 10598, United States., Vázquez FX; Computational Biology Center, IBM Thomas J. Watson Research Center , Yorktown Heights, New York 10598, United States., Zhang L; Computational Biology Center, IBM Thomas J. Watson Research Center , Yorktown Heights, New York 10598, United States., Das P; Computational Biology Center, IBM Thomas J. Watson Research Center , Yorktown Heights, New York 10598, United States., Toledo-Sherman L; CHDI Management/CHDI Foundation , Los Angeles, California 90045, United States., Luan B; Computational Biology Center, IBM Thomas J. Watson Research Center , Yorktown Heights, New York 10598, United States., Levitt M; Department of Structural Biology, Stanford University School of Medicine , Stanford, California 94305, United States., Zhou R; Computational Biology Center, IBM Thomas J. Watson Research Center , Yorktown Heights, New York 10598, United States.; Department of Chemistry, Columbia University , New York, New York 10027, United States.
Jazyk:	angličtina
Zdroj:	Journal of the American Chemical Society [J Am Chem Soc] 2017 Jul 05; Vol. 139 (26), pp. 8820-8827. Date of Electronic Publication: 2017 Jun 23.
DOI:	10.1021/jacs.7b00838
Abstrakt:	There exists strong correlation between the extended polyglutamines (polyQ) within exon-1 of Huntingtin protein (Htt) and age onset of Huntington's disease (HD); however, the underlying molecular mechanism is still poorly understood. Here we apply extensive molecular dynamics simulations to study the folding of Htt-exon-1 across five different polyQ-lengths. We find an increase in secondary structure motifs at longer Q-lengths, including β-sheet content that seems to contribute to the formation of increasingly compact structures. More strikingly, these longer Q-lengths adopt supercompact structures as evidenced by a surprisingly small power-law scaling exponent (0.22) between the radius-of-gyration and Q-length that is substantially below expected values for compact globule structures (∼0.33) and unstructured proteins (∼0.50). Hydrogen bond analyses further revealed that the supercompact behavior of polyQ is mainly due to the "glue-like" behavior of glutamine's side chains with significantly more side chain-side chain H-bonds than regular proteins in the Protein Data Bank (PDB). The orientation of the glutamine side chains also tend to be "buried" inside, explaining why polyQ domains are insoluble on their own.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu