Novel structural mechanism of membrane remodelling caused by the protein
MakA from Vibrio cholerae

Date:
February 8, 2022
Source:
Umea University
Summary:
New research has led to the discovery of a pH-induced structural
mechanism of membrane remodeling caused by the protein MakA, a
subunit of the recently described alpha-pore-forming toxin from
the pathogenic bacterium Vibrio cholerae.



FULL STORY ========================================================================== Research performed at Umeaa University, Sweden, has led to the discovery
of a pH-induced structural mechanism of membrane remodelling caused by
the protein MakA, a subunit of the recently described a-pore-forming
toxin from the pathogenic bacterium Vibrio cholerae. Collaborating
scientists affiliated with MIMS and UCMR publish their new findings in
the journal eLife.


==========================================================================
All types of living cells are dependent on functional membranes. Proteins
that form pores in biological membranes are found in many different
contexts, including some bacterial toxins that promote infections and
can cause damage to target cells and organelles. Research in the group of Professor Sun Nyunt Wai at Department of Molecular Biology resulted in the initial discovery of the protein MakA as a motility-associated secreted
toxin from V. cholerae using the predatory model organism Caenorhabditis elegans and in vitro grown mammalian cell models. When MakA is secreted
with two other Mak proteins, it forms the MakA/B/E tripartite pore complex
in mammalian cell membranes as revealed, recently through biochemical
analyses and structural characterisation using X- ray crystallography
in collaboration with the research team led by Professor Karina Persson
at Department of Chemistry. This is typical of the proteins known as
"the a-pore-forming toxins," a superfamily of membrane pore-forming
protein toxins.

MakA alone may also attach to target cell membranes and be taken up
by cultured mammalian cells via endocytosis where it accumulates in
the endolysosomal membrane space. Endolysosomes are acidic organelles
that break down cellular macromolecules and recycle cellular building materials. The new research work provides strong evidence for how MakA interacts with membranes under acidic conditions. It was found that
the MakA protein appears to make tube-like structures and make the
acidic endolysosomal compartment leaky and not work correctly. Acidic conditions made MakA generate oligomers and changed membranes into
tube-like structures, which caused cells to lose their membranes. When
MakA bound to liposomes from cell lipid extracts at low pH, they formed
the tube-like structures.

These studies unravel the dynamics of tubular growth, which occurs in a
pH-, lipid-, and concentration-dependent manner. A model of the detailed protein- lipid structure was obtained by Cryo-EM analysis. The MakA action
is a fascinating example of a membrane remodeling structural process
triggered by pH-dependent change in the protein's conformation. It will
be of interest to a wide spectrum of scientists working on host-pathogen interactions, membrane modification, and macromolecular structure of
medically significant bacterial pathogens. From the perspective of
protein engineering and nanotube formation, it is suggested that the
current discoveries on how MakA causes lipid/protein spiral structures
might be relevant for protein/membrane engineering and synthetic biology.

The research was conducted at Umeaa University thanks to the collaboration
of several additional UCMR-affiliated research groups that contributed
their different competences. The project has benefitted greatly from
assistance provided by local and national research infrastructures:
Protein Expertise Platform (PEP), Biochemical Imaging Centre Umeaa
(BICU), Umeaa Core Facility for Electron Microscopy (UCEM) and the
National Microscopy Infrastructure (NMI). The research was supported by
grants from the Swedish Research Council, The Swedish Cancer Society,
The Kempe Foundations, the Faculty of Medicine at Umeaa University, the
Knut and Alice Wallenberg Foundation, the European Research Council, the SciLifeLab National Fellows programme, and The Laboratory for Molecular Infection Medicine Sweden (MIMS).

========================================================================== Story Source: Materials provided by Umea_University. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Aftab Nadeem, Alexandra Berg, Hudson Pace, Athar Alam, Eric Toh,
Jo"rgen
AAde'n, Nikola Zlatkov, Si Lhyam Myint, Karina Persson, Gerhard
Gro"bner, Anders Sjo"stedt, Marta Bally, Jonas Barandun, Bernt Eric
Uhlin, Sun Nyunt Wai. Protein-lipid interaction at low pH induces
oligomerization of the MakA cytotoxin from Vibrio cholerae. eLife,
2022; 11 DOI: 10.7554/ eLife.73439 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220208104901.htm
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