TMPRSS2 in microbial interactions: Insights from HKU1 and TcsH

PLoS Pathogens, Год журнала: 2024, Номер 20(11), С. e1012677 - e1012677

Опубликована: Ноя. 20, 2024

Transmembrane Serine Protease 2 (TMPRSS2), known primarily for its role as a protease, has emerged critical receptor microbial agents such human coronavirus HKU1 and exotoxin TcsH. utilizes both sialoglycan TMPRSS2 cellular entry, where primes the spike protein binding. undergoes autocleavage to enhance affinity spike, facilitating viral membrane fusion postcleavage. Interestingly, TMPRSS2’s catalytic function is dispensable TcsH interactions, suggesting alternative roles in pathogenesis. Structural insights highlight potential therapeutic targets against infections cancers, leveraging interactions drug development. Understanding interplay between microbes opens new avenues targeting developing treatments infections.

Язык: Английский

Unraveling Coronavirus Cell Invasion: The Role of Glycan Receptors in Human Coronavirus-HKU1 Cell Entry

Infectious Diseases & Immunity, Год журнала: 2024, Номер unknown

Опубликована: Дек. 12, 2024

Coronaviruses are enveloped RNA viruses distinguished by their crown-like surface spikes. These cause various diseases in humans and animals, including respiratory, gastrointestinal, neurological disorders. The health risks posed coronaviruses substantial, as demonstrated severe acute respiratory syndrome-coronavirus (SARS-CoV) SARS-CoV-2. SARS-CoV triggered a global outbreak of SARS 2003, SARS-CoV-2 has been responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic since end 2019. Furthermore, four human (HCoVs), HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, have implicated 15% to 30% cases common cold.[1] Given prevalence potential diseases, understanding mechanisms underlying invasion into cells is essential public health. By binding specific cell receptors, spike protein undergoes conformational changes that promote membrane fusion entry virus host cells. Although significant progress made elucidating entry, detailed molecular interactions between viral proteins receptors remain incompletely understood. A recent study Wang et al.[2] reported critical stage HCoV-HKU1 process: recognition glycan receptor N-terminal domain (NTD). This interaction induces change crucial exposing receptor-binding (RBD). Exposure RBD step precedes receptor, Transmembrane Protease Serine 2 (TMPRSS2). subsequent TMPRSS2 activates machinery, thereby facilitating (Figure 1). finding not only deepened complex dynamics but it also identifies targets development antiviral therapies. In context concurrent publications Cell, al. provided novel perspective. While McCallum concentrated on protein-TMPRSS2 interaction, revealed synergistic role invasion, mechanism previously explored al.[3] findings align with emphasis Fernández activation HKU1 recognition.[4] synergy TMPRSS2, comprehensive view invasion.Figure 1: Proposed model (CoV)-HKU1 engagement. interacts 9-O-acetylsialic acid (9-O-Ac-Sia) via its triggers an allosteric opening adjacent (RBD), which facilitates protease, figure was created using BioRender.HCoV-HKU1 notable pathogen causes cold, worldwide. involves trimeric glycoprotein proteinaceous receptors.[5,6] Similar Middle East syndrome (MERS)-CoV, uses within C-terminal S1 subunit interact receptors. contrast, bind NTD protein. inducing RBD.[7] exposed then leading thus cell. Notably, determined structures 9-O-Ac-Sia cryo-electron microscopy, interface RBD. Through meticulous examination conserved amino acids, specifically residues 505, 509, 515, 517, 528 HCoV-HKU1A/C 461, 469, 470 at HKU1A HKU1C followed series experiments, functional importance these pivotal adeptly confirmed. precise investigation elucidated virus-host interactions, offering profound insights underpinnings conducted sequence analysis across 23 species. They discovered species, camel, alpaca, rat, monkey, pig, whose possess key residues, identical those interface, had stronger affinity highlight evolutionary conservation sites impact ability offer new hosts HCoV-HKU1. readily mutations, particularly protein, potentially altering infectivity antigenicity virus, subsequently impacting effectiveness neutralizing antibodies vaccines. An array approaches used combat coronaviruses,[8,9] suggesting combination antibodies, vaccines, drugs, or both, simultaneously targeting TMPRSS2- sialoglycan-binding sites, could achieve potent effect. Building previous studies, this discovery highlights infection mechanism. involvement initial stages attachment facilitation indicate interplay success. Understanding participate will enhance knowledge pathogenesis assist innovative strategies. primary glycans involved, include sialic acid, heparan sulfate, chondroitin sulfate proteoglycans, histo-blood group antigens. coronaviruses, heparin commonly during specificity tropism pathogenicity.[10] Numerous structural studies sugar-protein facilitate viruses, enhancing our glycan-protein pioneering study, Hulswit basis HCoV-OC43 protein.[5] Simultaneously, Park features α-2,3- α-2,6-linked acids MERS-CoV Their work enriched diverse glycan-binding patterns may influence tropism.[11] Liu delineated revealing exploits establish cells.[12] Previous local long-range upon sialoglycan-based NTD. shift, transition open state ("up") through interdomain allowing secondary binding.[7] However, changes, unclear. 2023, Saunders identified findings, question arose whether induced sialoglycan influences HCoV-HKU1.[6] description highlighting interfaces involving 9-O-Ac-Sia, TMPRSS2.[2] Gao similar regarding proposed updated dual receptor-based cell, providing more insights.[13] Similarly, seminal 2020 published Cell play exposure RBD, assisting receptor. suggests serves It shown triggering effectively opens structure allows angiotensin converting enzyme receptor.[12] Since virus-receptor infection, such prevent action implications drug development. Targeting disrupt necessary binding. Additionally, aid design small molecules block engage Zeng further required determine other use Acknowledgments None. Funding supported grants from Key Technologies Research Development Program (2022YFC3400900), Postdoctoral Fellowship CPSF (GZB20230886), China Science Foundation (2023M743998), National Natural (82030046), Guangdong Introducing Innovative Entrepreneurial Teams (2019BT02Y198), Technology Department (2020B1212030004). Author Contributions Yan-Lin Yang conceptualization writing research highlight, ensuring were accurately summarized communicated. Zheng-Zhou Lu, Chu Xie Lan-Yi Zhong scientific suggestions manuscript revision. Cong Sun contributed conceptualization, creating figures, reviewing manuscript, visual appeal accuracy presented information. Mu-Sheng expert supervision, reviewing, editing highlight. All authors read approved final manuscript. Conflicts Interest

Язык: Английский

High-resolution crystal structure of human coronavirus HKU1 receptor binding domain bound to TMPRSS2 receptor

hLife, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

Язык: Английский