Cell . TMPRSS2 and glycan receptors synergistically facilitate coronavirus entry

[tetano]

Cell


. 2024 Jun 21:S0092-8674(24)00656-1.
doi: 10.1016/j.cell.2024.06.016. Online ahead of print. TMPRSS2 and glycan receptors synergistically facilitate coronavirus entry

Haofeng Wang ¹ , Xiaoce Liu ¹ , Xiang Zhang ² , Zhuoqian Zhao ³ , Yuchi Lu ³ , Dingzhe Pu ⁴ , Zeyang Zhang ³ , Jie Chen ¹ , Yajie Wang ² , Mengfei Li ¹ , Xuxue Dong ⁴ , Yinkai Duan ¹ , Yujia He ¹ , Qiyu Mao ² , Hangtian Guo ⁵ , Haoran Sun ¹ , Yihan Zhou ¹ , Qi Yang ⁶ , Yan Gao ¹ , Xiuna Yang ¹ , Hongzhi Cao ⁷ , Luke Guddat ⁸ , Lei Sun ⁹ , Zihe Rao ¹⁰ , Haitao Yang ¹¹



Affiliations

• PMID: 38964329
• DOI: 10.1016/j.cell.2024.06.016

Abstract

The entry of coronaviruses is initiated by spike recognition of host cellular receptors, involving proteinaceous and/or glycan receptors. Recently, TMPRSS2 was identified as the proteinaceous receptor for HCoV-HKU1 alongside sialoglycan as a glycan receptor. However, the underlying mechanisms for viral entry remain unknown. Here, we investigated the HCoV-HKU1C spike in the inactive, glycan-activated, and functionally anchored states, revealing that sialoglycan binding induces a conformational change of the NTD and promotes the neighboring RBD of the spike to open for TMPRSS2 recognition, exhibiting a synergistic mechanism for the entry of HCoV-HKU1. The RBD of HCoV-HKU1 features an insertion subdomain that recognizes TMPRSS2 through three previously undiscovered interfaces. Furthermore, structural investigation of HCoV-HKU1A in combination with mutagenesis and binding assays confirms a conserved receptor recognition pattern adopted by HCoV-HKU1. These studies advance our understanding of the complex viral-host interactions during entry, laying the groundwork for developing new therapeutics against coronavirus-associated diseases.

Keywords: HCoV-HKU1; TMPRSS2; glycan receptor; proteinaceous receptor; viral entry.

[tetano]

Cell


. 2024 Jun 26:S0092-8674(24)00646-9.
doi: 10.1016/j.cell.2024.06.006. Online ahead of print. Human coronavirus HKU1 recognition of the TMPRSS2 host receptor

Matthew McCallum ¹ , Young-Jun Park ² , Cameron Stewart ¹ , Kaitlin R Sprouse ² , Amin Addetia ¹ , Jack Brown ¹ , M Alejandra Tortorici ¹ , Cecily Gibson ² , Emily Wong ³ , Margareta Ieven ⁴ , Amalio Telenti ³ , David Veesler ⁵



Affiliations

• PMID: 38964328
• DOI: 10.1016/j.cell.2024.06.006

Abstract

The human coronavirus HKU1 spike (S) glycoprotein engages host cell surface sialoglycans and transmembrane protease serine 2 (TMPRSS2) to initiate infection. The molecular basis of HKU1 binding to TMPRSS2 and determinants of host receptor tropism remain elusive. We designed an active human TMPRSS2 construct enabling high-yield recombinant production in human cells of this key therapeutic target. We determined a cryo-electron microscopy structure of the HKU1 RBD bound to human TMPRSS2, providing a blueprint of the interactions supporting viral entry and explaining the specificity for TMPRSS2 among orthologous proteases. We identified TMPRSS2 orthologs from five mammalian orders promoting HKU1 S-mediated entry into cells along with key residues governing host receptor usage. Our data show that the TMPRSS2 binding motif is a site of vulnerability to neutralizing antibodies and suggest that HKU1 uses S conformational masking and glycan shielding to balance immune evasion and receptor engagement.

Keywords: HKU1; TMPRSS2; coronaviruses; glycan shielding; immune evasion; neutralizing antibodies; species tropism; spike glycoprotein.

[tetano]

Cell


. 2024 Jun 21:S0092-8674(24)00647-0.
doi: 10.1016/j.cell.2024.06.007. Online ahead of print. Structural basis of TMPRSS2 zymogen activation and recognition by the HKU1 seasonal coronavirus

Ignacio Fernández ¹ , Nell Saunders ² , Stéphane Duquerroy ³ , William H Bolland ² , Atousa Arbabian ¹ , Eduard Baquero ⁴ , Catherine Blanc ⁵ , Pierre Lafaye ⁶ , Ahmed Haouz ⁷ , Julian Buchrieser ² , Olivier Schwartz ⁸ , Félix A Rey ⁹



Affiliations

• PMID: 38964326
• DOI: 10.1016/j.cell.2024.06.007

Abstract

The human seasonal coronavirus HKU1-CoV, which causes common colds worldwide, relies on the sequential binding to surface glycans and transmembrane serine protease 2 (TMPRSS2) for entry into target cells. TMPRSS2 is synthesized as a zymogen that undergoes autolytic activation to process its substrates. Several respiratory viruses, in particular coronaviruses, use TMPRSS2 for proteolytic priming of their surface spike protein to drive membrane fusion upon receptor binding. We describe the crystal structure of the HKU1-CoV receptor binding domain in complex with TMPRSS2, showing that it recognizes residues lining the catalytic groove. Combined mutagenesis of interface residues and comparison across species highlight positions 417 and 469 as determinants of HKU1-CoV host tropism. The structure of a receptor-blocking nanobody in complex with zymogen or activated TMPRSS2 further provides the structural basis of TMPRSS2 activating conformational change, which alters loops recognized by HKU1-CoV and dramatically increases binding affinity.

Keywords: 3D structure; TMPRSS2 inhibition; androgen-regulated proteases; entry receptor; human coronaviruses; serine protease activation; spike maturation; virus entry; zymogen triad.