ACE2, B0AT1, and SARS-CoV-2 spike protein: Structural and functional implications

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a public health crisis and led to tremendous economic devastation. The spike protein (S) of SARS-CoV-2 hijacks the angiotensin converting enzyme 2 (ACE2) as a receptor for virus entry, representing the initial step of viral infection. S is one of the major targets for development of the antiviral drugs, antibodies, and vaccines. ACE2 is a peptidase that plays a physiologically important role in the renin-angiotensin system. Concurrently, it also forms dimer of heterodimer with the neutral amino acid transporter B⁰AT1 to regulate intestinal amino acid metabolism. The symptoms of COVID-19 are closely correlated with the physiological functions of ACE2. In this review, we summarize the functional and structural studies on ACE2, B⁰AT1, and their complex with S of SARS-CoV-2, providing insights into the various symptoms caused by viral infection and the development of therapeutic strategies.

Figure 1

Schematic diagram of multi-functional ACE2. ACE2 plays a major role in the renin–angiotensin system by cleaving Ang II to Ang-(1–7) or Ang I to Ang-(1–9) (pink inset), which can decrease blood pressure and relax blood vessels. ACE2 is also a chaperone for the neutral amino acid transporter B⁰AT1 in small intestine. Besides, ACE2 acts as a receptor for multiple viruses, such as SARS-CoV-2 or SARS-CoV-1. Dozens of S are localized on the surface of SARS-CoV-2 virion. RBD of S can be in “down” and “up” conformation. Only the “up” conformation allows RBD to bind ACE2. Full-length ACE2 on cell membrane is cleaved by ADAM17 or TMPRSS2. After being shed by ADAM17, soluble ACE2 (sACE2) is released into extracellular side, which remains the enzymatic activity and the ability to bind SARS-CoV-2, can prevent the virus from invading host cells and spreading. The trimeric S is cleaved by furin or furin-like proprotein convertase into the S1 and S2 subunits during viral assembly in the infected cells. Binding to ACE2 on cell membrane induces the “up” conformation of RBD, which facilitates the shedding of the S1-ACE2 complex. S2 undergoes conformational changes to trigger the membrane fusion. S means spike protein; Ang means angiotensin. ACE2 dimer: red and wheat; B⁰AT1 dimer: deep blue and violet; S trimer: cyan, gray and orange; ADAM17: blue; TMPRSS2: red-orange; furin: blue.

Figure 2

Cryo-EM structures of the ACE2-B⁰AT1 complex and their complex with RBD or S of SARS-CoV-2. The ACE2-B⁰AT1 complex exists as a dimer of heterodimer, with two dimerization interfaces mediated by PD (①) or CLD (②) of ACE2, respectively. The disruption of PD dimerization interface induces ACE2 changing from a closed state to an open state. CLD of ACE2 binds to TM7 of B⁰AT1 that extends to the extracellular. Each monomer in the dimeric ACE2 molecule can be bound by a RBD or an S of SARS-CoV-2. The binding interface between RBD of SARS-CoV-2 and ACE2 is mainly mediated by polar interactions, with the extended loop region of RBD spanning the α1 helix of PD of ACE2 like a bridge. S means spike protein, RBD means receptor binding domain, TM means transmembrane, PD means peptidase domain and CLD means collectrin-like domain. ACE2 dimer is colored as red and wheat; B⁰AT1 dimer is colored as deep blue and violet; RBD is colored as cyan; S trimer is colored as cyan, gray, and orange.