TMPRSS2 in microbial interactions: Insights from HKU1 and TcsH

Abstract

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

Fig 1. Diagram illustrating the role of TMPRSS2 in the cellular entry of TcsH and HKU1.

For TcsH: Both TMPRSS2 and fucosylated glycans act as receptors for TcsH, facilitating its entry. TcsH utilizes its CROP domain to bind with TMPRSS2. For HKU1: TMPRSS2, initially synthesized as an inactive zymogen on the plasma membrane, undergoes autocleavage for maturation, thereby enhancing its binding affinity to the HKU1 spike. Sialoglycan functions as the glycan receptor for HKU1, alleviating steric hindrance upon binding and promoting an “open” conformation of the spike’s RBD, which facilitates spike binding. TMPRSS2 serves as the protein receptor that facilitates HKU1 entry into host cells. In addition to its role as a receptor, TMPRSS2 catalytically cleaves the spike at S2’ site, preparing it for fusion.

Fig 2. Superimposed structures of the HKU1A spike–TMPRSS2 interface and the TcsH–TMPRSS2 interface.

The left panel displays the binding interfaces of the HKU1A spike and TcsH proteins with TMPRSS2. The right panel shows cartoon representations of the enlarged views of the HCoV-HKU1A spike (top) and TcsH (bottom) at the TMPRSS2 interface. The green area indicates the binding interface of the HKU1A spike on TMPRSS2, involving amino acids 256–491. The purple-red region represents the binding interface of TcsH on TMPRSS2, which includes residues 142–492. The residues L419 and W461 on TMPRSS2, labeled in red, are shared interaction residues for both the HKU1A spike and TcsH. The three-dimensional structures are derived from the structure of HCoV-HKU1A spike in the functionally anchored-3up conformation with 3TMPRSS2 (PDB ID: 8Y7X) and the Cryo-EM structure of the TcsH–TMPRSS2 complex (PDB ID: 8JHZ), generated using Discovery Studio 2016 Client and PyMOL 2.3.