Structural insight into host plasma membrane association and assembly of HIV-1 matrix protein

Oligomerization of Pr55 Gag is a critical step of the late stage of the HIV life cycle. It has been known that the binding of IP6, an abundant endogenous cyclitol molecule at the MA domain, has been linked to the oligomerization of Pr55 Gag . However, the exact binding site of IP6 on MA remains unkn...

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Bibliographic Details
Published in:	Scientific reports Vol. 11; no. 1; pp. 15819 - 14
Main Authors:	Ciftci, Halilibrahim, Tateishi, Hiroshi, Koiwai, Kotaro, Koga, Ryoko, Anraku, Kensaku, Monde, Kazuaki, Dağ, Çağdaş, Destan, Ebru, Yuksel, Busra, Ayan, Esra, Yildirim, Gunseli, Yigin, Merve, Ertem, F. Betul, Shafiei, Alaleh, Guven, Omur, Besler, Sabri O., Sierra, Raymond G., Yoon, Chun Hong, Su, Zhen, Liang, Mengling, Acar, Burcin, Haliloglu, Turkan, Otsuka, Masami, Yumoto, Fumiaki, Fujita, Mikako, Senda, Toshiya, DeMirci, Hasan
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 04-08-2021 Nature Publishing Group Nature Portfolio
Subjects:	60 APPLIED LIFE SCIENCES 631/535 631/535/1266 Binding Sites Cell Membrane - metabolism Crystallography Crystallography, X-Ray Entropy HIV HIV Infections - metabolism HIV Infections - pathology HIV Infections - virology HIV-1 - physiology Human immunodeficiency virus Humanities and Social Sciences Humans Life cycles Localization Matrix protein Models, Molecular multidisciplinary Oligomerization Phosphatidylinositol 4,5-diphosphate Phosphoric Monoester Hydrolases - metabolism Protein Conformation Protein Domains Protein Precursors - chemistry Protein Precursors - metabolism Science Science (multidisciplinary) Structural biology Virions Virus Assembly X-ray crystallography
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Summary:	Oligomerization of Pr55 Gag is a critical step of the late stage of the HIV life cycle. It has been known that the binding of IP6, an abundant endogenous cyclitol molecule at the MA domain, has been linked to the oligomerization of Pr55 Gag . However, the exact binding site of IP6 on MA remains unknown and the structural details of this interaction are 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 GNM-based transfer entropy calculations 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 binding of Pr55 Gag to membrane. 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 IP6 coordination of the oligomerization of outer MA and inner CA domain’s 2D layers during assembly and budding.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 USDOE Office of Science (SC), Basic Energy Sciences (BES) AC02-76SF00515
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-021-95236-8