Hok, L. | bioRxiv Science

bioRxiv2024

Structural Basis of Non-Latent Signaling by the Anti-Mullerian Hormone Procomplex

Most TGF{beta} family ligands exist as procomplexes consisting of a prodomain noncovalently bound to a growth factor (GF); Whereas some prodomains confer latency, the Anti-Mullerian Hormone (AMH) prodomain maintains a remarkably high affinity for the GF yet remains active. Using single particle EM methods, we show the AMH prodomain consists of two subdomains: a vestigial TGF{beta} prodomain-like fold and a novel, helical bundle GF-binding domain, the result of an exon insertion 450 million years ago, that engages both receptor epitopes. When associated with the prodomain, the AMH GF is distorted into a strained, open conformation whose closure upon bivalent binding of AMHR2 displaces the prodomain through a conformational shift mechanism to allow for signaling.

molecular biology↗

bioRxiv2021

Relationship between COVID-19 infection and neurodegeneration: Computational insight into interactions between the SARS-CoV-2 spike protein and the monoamine oxidase enzymes

Although COVID-19 has been primarily associated with pneumonia, recent data show that its causative agent, the SARS-CoV-2 coronavirus, can infect many vital organs beyond the lungs, including the heart, kidneys and the brain. The literature agrees that COVID-19 is likely to have long-term mental health effects on infected individuals, which signifies a need to understand the role of the virus in the pathophysiology of brain disorders that is currently unknown and widely debated. Our docking and molecular dynamic simulations show that the affinity of the spike protein from the wild type (WT) and the South African B.1.351 (SA) variant towards the MAO enzymes is comparable to that for its ACE2 receptor. This allows for the WT/SA...MAO complex formation, which changes MAO affinities for their neurotransmitter substrates, thus consequently impacting the rates of their metabolic conversion and misbalancing their levels. Knowing that this fine regulation is strongly linked with the etiology of various brain pathologies, these results are the first to highlight the possibility that the interference with the brain MAO catalytic activity is responsible for the increased neurodegenerative illnesses following a COVID-19 infection, thus placing a neurobiological link between these two conditions in the spotlight. Since the obtained insight suggests that a more contagious SA variant causes even larger disturbances, and with new and more problematic strains likely emerging in the near future, we firmly advise that the presented prospect of the SARS-CoV-2 induced neurological complications should not be ignored, but rather requires further clinical investigations to achieve an early diagnosis and timely therapeutic interventions. TABLE OF CONTENTS ENTRY O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/458208v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1976c81org.highwire.dtl.DTLVardef@54bb35org.highwire.dtl.DTLVardef@cea31aorg.highwire.dtl.DTLVardef@364100_HPS_FORMAT_FIGEXP M_FIG C_FIG Docking and molecular dynamic simulations highlight the possibility that the interference with the brain monoamine oxidase (MAO) catalytic activity is responsible for the increased neurodegenerative illnesses following a COVID-19 infection.

molecular biology↗