A comprehensive in silico analysis of huntingtin and its interactome.

A polyglutamine expansion of the N-terminal region of huntingtin (Htt) causes Huntington’s disease, a severe neurodegenerative disorder. Htt huge multidomain structure, the presence of disordered regions, and the lack of sequence homologs of known structure, so far prevented structural studies of Htt, making the study of its structure-function relationships very difficult. In this work, the presence and location of five Htt ordered domains (named from Hunt1 to Hunt5) has been detected and the structure of these domains has been predicted for the first time using a combined threading/ab initio modeling approach. This work has led to the identification of a previously undetected HEAT repeats region in the Hunt3 domain. Furthermore, a putative function has been assigned to four out of the five domains. Hunt1 and Hunt5, displaying structural similarity with the regulatory subunit A of protein phosphatase 2A, are predicted to play a role in regulating the phosphorylation status of cellular proteins. Hunt2 and Hunt3 are predicted to be homologs of two yeast importins and to mediate vescicles transport and protein trafficking. Finally, a comprehensive analysis of the Htt interactome has been carried out and is discussed to provide a global picture of the Htt’s structure–function relationships.