Journal Article

The cryo-electron microscopy structure of huntingtin

Bin Huang, Oeckl, Patrick, Baumeister, Wolfgang, Seefelder, Manuel, Pautsch, Alexander, Kochanek, Stefan, Moser, Franziska, Otto, Markus, Pfeifer, Günter, Fernández-Busnadiego, Rubén, Engler, Tatjana, Guo, Qiang, Cheng, Jingdong, Maurer, Melanie

2018

Overview

The structure of huntingtin in complex with an interactor is determined to an overall resolution of 4 Å, paving the way for improved understanding of the cellular functions of this protein. The structure of Huntingtin Huntingtin (HTT) is a large protein, essential for embryonic development and involved in diverse cellular activities such as vesicular transport, endocytosis, autophagy and transcription regulation. The large number of HTT interactors that have been identified suggests that HTT is at the centre of a protein–protein interaction hub. A mutation in the HTT gene results in the expansion of a polyglutamine repeat at the N-terminus of HTT and in Huntington's disease. Stefan Kochanek and colleagues present the full-length structure of human HTT in a complex with HAP40 to 4 Å resolution. This detailed structure paves the way for an improved understanding of the diverse cellular functions of HTT. Huntingtin (HTT) is a large (348 kDa) protein that is essential for embryonic development and is involved in diverse cellular activities such as vesicular transport, endocytosis, autophagy and the regulation of transcription 1 , 2 . Although an integrative understanding of the biological functions of HTT is lacking, the large number of identified HTT interactors suggests that it serves as a protein–protein interaction hub 1 , 3 , 4 . Furthermore, Huntington’s disease is caused by a mutation in the HTT gene, resulting in a pathogenic expansion of a polyglutamine repeat at the amino terminus of HTT 5 , 6 . However, only limited structural information regarding HTT is currently available. Here we use cryo-electron microscopy to determine the structure of full-length human HTT in a complex with HTT-associated protein 40 (HAP40; encoded by three F8A genes in humans) 7 to an overall resolution of 4 Å. HTT is largely α-helical and consists of three major domains. The amino- and carboxy-terminal domains contain multiple HEAT (huntingtin, elongation factor 3, protein phosphatase 2A and lipid kinase TOR) repeats arranged in a solenoid fashion. These domains are connected by a smaller bridge domain containing different types of tandem repeats. HAP40 is also largely α-helical and has a tetratricopeptide repeat-like organization. HAP40 binds in a cleft and contacts the three HTT domains by hydrophobic and electrostatic interactions, thereby stabilizing the conformation of HTT. These data rationalize previous biochemical results and pave the way for improved understanding of the diverse cellular functions of HTT.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/1 / 101/28 / 101/58 / 13 / 13/106 / 13/109 / 631/378/1689/1558 / 631/378/340 / 631/45/612/1246 / 631/57/2265 / 692/617/375/1558 / 82/1 / 82/16 / 82/29 / 82/58 / 82/80 / 82/83 / Autophagy / Cryoelectron Microscopy / Electron microscopy / Electrostatic properties / Elongation / Embryogenesis / Embryonic growth stage / Endocytosis / Gene regulation / Humanities and Social Sciences / Humans / Huntingtin / Huntingtin Protein - chemistry / Huntingtin Protein - metabolism / Huntingtin Protein - ultrastructure / Huntington's disease / Huntingtons disease / Hydrophobic and Hydrophilic Interactions / Hydrophobicity / Kinases / letter / Lipid kinase / Microscopy / Models, Molecular / multidisciplinary / Mutation / Nuclear Proteins - chemistry / Nuclear Proteins - metabolism / Nuclear Proteins - ultrastructure / Phagocytosis / Phosphoprotein phosphatase / Phosphorylation / Physiological aspects / Polyglutamine / Protein Binding / Protein Domains / Protein interaction / Protein phosphatase / Protein Structure, Secondary / Proteins / Science / Static Electricity / Structure / Transcription / Transmission electron microscopy / Trinucleotide repeat diseases