Structural insight into host plasma membrane association and assembly of HIV-1 Matrix protein
Category
Published on
Type
posted-content
Author
Halilibrahim Ciftci and Hiroshi Tateishi and Kotaro Koiwai and Ryoko Koga and Kensaku Anraku and Kazuaki Monde and Çağdaş Dağ and Ebru Destan and Busra Yuksel and Esra Ayan and Gunseli Yildirim and Merve Yigin and F. Betul Ertem and Alaleh Shafiei and Omur Guven and Sabri O. Besler and Raymond G. Sierra and Chun Hong Yoon and Zhen Su and Mengling Liang and Burcin Acar and Turkan Haliloglu and Masami Otsuka and Fumiaki Yumoto and Mikako Fujita and Toshiya Senda and Hasan DeMirci
Citation
Ciftci, H. et al., 2021. Structural insight into host plasma membrane association and assembly of HIV-1 Matrix protein. Available at: http://dx.doi.org/10.1101/2021.02.21.432153.
Abstract
ABSTRACTHIV-1 continues to be a global health concern since AIDS was first recognized by the World Health Organization (WHO). It is estimated that there were 38 million people infected with HIV-1 and 1.5 million deaths in 2019 alone. A better understanding of the details of the HIV late-stage life cycle, involving Pr55Gag attachment to the membrane for the further oligomerization to release virion, will provide us new avenues for potential treatment. Inositol hexakisphosphate (IP6) is an abundant endogenous cyclitol molecule and its binding was linked to the oligomerization of Pr55Gag via the MA domain. However, the binding site of IP6 on MA was unknown and the structural details of this interaction were missing. Here, we present three high-resolution crystal structures of the MA domain in complex with IP6 molecules to reveal its binding mode. Additionally, extensive Differential Scanning Fluorimetry analysis combined with cryo- and ambient-temperature X-ray crystallography and computational biology identify the key residues that participate in IP6 binding. Our data provide novel insights about the multilayered HIV-1 virion assembly process that involves the interplay of IP6 with PIP2, a phosphoinositide essential for the membrane binding of Pr55Gag. IP6 and PIP2 have neighboring alternate binding sites within the same highly basic region (residues 18-33). This indicates that IP6 and PIP2 bindings are not mutually exclusive and may play a key role in coordinating virion particles’ membrane localization. Based on our three different IP6-MA complex crystal structures, we propose a new model that involves the IP6 coordination of the oligomerization of outer MA and inner CA domain 2D layers during assembly and budding.
DOI
Funding
NSF-STC Biology with X-ray Lasers (NSF-1231306)
