Jian Payandeh

Exelixis (United States)

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Christopher P. Arthur

University of Bristol

Claudio Ciferri

Kaiser Permanente South San Francisco Medical Center

Christopher M. Koth

Denali Therapeutics (United States)

Alexis Rohou

Imperial College London

David H. Hackos

Roche (United States)

Hoangdung Ho

Sea Lane Biotechnologies (United States)

Marc Kschonsak

European Molecular Biology Laboratory

E.F. Pai

Princess Margaret Cancer Centre

Christine Tam

Molecular Research Institute

Ning Zheng

University of Washington

Cooperative Institutions

Genentech

132

University of California, San Francisco

Kaiser Permanente South San Francisco Medical Center

Stanford University

University of Washington

Howard Hughes Medical Institute

University of California, Berkeley

Roche (United States)

Harvard University

Roche (Switzerland)

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Progress in understanding slow inactivation speeds up

The Journal of General Physiology (2018)

Jian Payandeh

A new study reveals that conformational flexibility in the pore of a voltage-gated sodium channel may underlie slow inactivation.

10.1085/jgp.201812149

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Citations (8)

Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer’s disease

bioRxiv (Cold Spring Harbor Laboratory) (2018)

Nisha Rathore Sree R. Ramani Homer Pantua Jian Payandeh Tushar Bhangale

Abstract Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) is a cell surface inhibitory receptor that recognizes specific O -glycosylated proteins and is expressed on various innate immune cell types including microglia. We show here that a common missense variant (G78R, rs1859788) of PILRA is the likely causal allele for the confirmed Alzheimer’s disease risk locus at 7q21 (rs1476679). The G78R variant alters the interaction of residues essential for sialic acid engagement, resulting in >50% reduced binding for several PILRA ligands including a novel ligand, complement component 4A, and herpes simplex virus 1 (HSV-1) glycoprotein B. PILRA is an entry receptor for HSV-1 via glycoprotein B, and macrophages derived from R78 homozygous donors showed significantly decreased levels of HSV-1 infection at several multiplicities of infection compared to homozygous G78 macrophages. We propose that PILRA G78R protects individuals from Alzheimer’s disease risk via reduced inhibitory signaling in microglia and reduced microglial infection during HSV-1 recurrence.

10.1101/325936

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Probing Structure-Function Relationships and Gating Mechanisms in the CorA Mg2+ Transport System

Journal of Biological Chemistry (2008)

Jian Payandeh Canhui Li Mohabir Ramjeesingh Ewa Poduch Christine E. Bear

Recent crystal structures of the CorA Mg(2+) transport protein from Thermotoga maritima (TmCorA) revealed an unusually long ion pore putatively gated by hydrophobic residues near the intracellular end and by universally conserved asparagine residues at the periplasmic entrance. A conformational change observed in an isolated funnel domain structure also led to a proposal for the structural basis of gating. Because understanding the molecular mechanisms underlying ion channel and transporter gating remains an important challenge, we have undertaken a structure-guided engineering approach to probe structure-function relationships in TmCorA. The intracellular funnel domain is shown to constitute an allosteric regulatory module that can be engineered to promote an activated or closed state. A periplasmic gate centered about a proline-induced kink of the pore-lining helix is described where "helix-straightening" mutations produce a dramatic gain-of-function. Mutation to the narrowest constriction along the pore demonstrates that a hydrophobic gate is operational within this Mg(2+)-selective transport protein and likely forms an energetic barrier to ion flux. We also provide evidence that highly conserved acidic residues found in the short periplasmic loop are not essential for TmCorA function or Mg(2+) selectivity but may be required for proper protein folding and stability. This work extends our gating model for the CorA-Alr1-Mrs2 superfamily and reveals features that are characteristic of an ion channel. Aspects of these results that have broader implications for a range of channel and transporter families are highlighted.

Thermotoga maritima

Transport protein

Helix (gastropod)

Folding (DSP implementation)

10.1074/jbc.m707889200

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Citations (70)

Monoclonal antibody targeting the β-barrel assembly machine of Escherichia coli is bactericidal

Proceedings of the National Academy of Sciences (2018)

Kelly M. Storek Marcy R. Auerbach Handuo Shi Natalie K. Garcia Dawei Sun

Significance The outer membrane of Gram-negative bacteria presents a formidable barrier to the discovery of new antibiotics needed to combat infections by multidrug-resistant bacteria. Targeting essential proteins or processes directly exposed to the environment could bypass this obstacle. Here, we describe a monoclonal antibody that selectively and potently antagonizes BamA, which folds and inserts integral outer membrane β-barrel proteins, by binding to a surface-exposed BamA epitope and, as a result, inhibits bacterial cell growth. Mechanisms of resistance to the antibody reveal that membrane fluidity affects BamA activity. This antibody validates the potential therapeutic strategy of targeting essential, exposed functions and provides a powerful tool for dissecting the fundamental process of folding integral membrane β-barrel proteins in vivo.

Bama

10.1073/pnas.1800043115

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Citations (155)

The discovery and structural basis of two distinct state-dependent inhibitors of BamA

Nature Communications (2024)

Dawei Sun Kelly M. Storek Dimitry Tegunov Ying Yang Christopher P. Arthur

BamA is the central component of the essential β-barrel assembly machine (BAM), a conserved multi-subunit complex that dynamically inserts and folds β-barrel proteins into the outer membrane of Gram-negative bacteria. Despite recent advances in our mechanistic and structural understanding of BamA, there are few potent and selective tool molecules that can bind to and modulate BamA activity. Here, we explored in vitro selection methods and different BamA/BAM protein formulations to discover peptide macrocycles that kill Escherichia coli by targeting extreme conformational states of BamA. Our studies show that Peptide Targeting BamA-1 (PTB1) targets an extracellular divalent cation-dependent binding site and locks BamA into a closed lateral gate conformation. By contrast, PTB2 targets a luminal binding site and traps BamA into an open lateral gate conformation. Our results will inform future antibiotic discovery efforts targeting BamA and provide a template to prospectively discover modulators of other dynamic integral membrane proteins.

Bama

Basis (linear algebra)

10.1038/s41467-024-52512-1

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Citations (3)

Structure of an essential inner membrane protein–LPS complex

Acta Crystallographica Section A Foundations and Advances (2018)

Thomas Clairfeuille Kerry R. Buchholz Jian Payandeh Steven T. Rutherford

10.1107/s2053273318092069

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Citations (0)

Structural basis of alpha-scorpion toxin action on Navchannels.