Possible Co-Evolution of Polyglutamine and Polyproline in Huntingtin Protein: Proline-Rich Domain as Transient Folding Chaperone

被引：6

作者：

Zhang, Leili ^{[1
]}

Kang, Hongsuk ^{[1
,4
,5
]}

Perez-Aguilar, Jose Manuel ^{[6
]}

Zhou, Ruhong ^{[1
,2
,3
]}

机构：

[1] Computat Biol Ctr, IBM Thomas J Watson Res Ctr, Yorktown Hts, NY 10598 USA

[2] Zhejiang Univ, Inst Quantitat Biol, Coll Life Sci, Hangzhou 310027, Peoples R China

[3] Columbia Univ, Dept Chem, New York, NY 10027 USA

[4] Univ Maryland, Natl Inst Sci & Technol, 100 Bur Dr, Gaithersburg, MD 20899 USA

[5] Univ Maryland, Inst Biosci & Biotechnol Res, 9600 Gudelsky Dr, Rockville, MD 20850 USA

[6] Meritorious Autonomous Univ Puebla BUAP, Sch Chem Sci, Puebla 72570, Mexico

来源：

JOURNAL OF PHYSICAL CHEMISTRY LETTERS | 2022年 / 13卷 / 27期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

EXON-1; N-TERMINUS; FLANKING SEQUENCES; HELICAL STRUCTURE; AGGREGATION; LENGTH; MECHANISM; MODULATE; POLYQ; DEATH; ASSOCIATION;

D O I：

10.1021/acs.jpclett.2c01184

中图分类号：

O64 [物理化学（理论化学）、化学物理学];

学科分类号：

070304 ; 081704 ;

摘要：

Huntington's disease is an inherited neurodegenerative disorder caused by the overduplication of CAG repeats in the Huntingtin gene. Recent findings revealed that among the orthologs, the expansion of CAG repeats (polyQ) in the Huntingtin gene occurs in tandem with the duplication of CCG repeats (polyP). However, the molecular mechanism of this possible co-evolution remains unknown. We examined the structures of Huntingtin exon 1 (HttEx1) from six species along with five designed mutants. We found that the polyP segments "chaperone" the rest of the HttExl by forming ad hoc polyP binding grooves. Such a process elongates the otherwise poorly solvated polyQ domain, while modulating its secondary structure propensity from beta-strands to alpha-helices. This chaperoning effect is achieved mostly through transient hydrogen bond interactions between polyP and the rest of HttEx1, resulting in a striking golden ratio of similar to 2:1 between the chain lengths of polyQ and polyP.

引用

页码：6331 / 6341

页数：11