How viruses use ‘fake’ proteins to hide in our cells
Some viruses can hide in our bodies for decades. They make ‘fake’ human proteins that trick our immune cells into thinking ‘everything is awesome’, there’s nothing to see here.
Now researchers at the Imaging Centre of Excellence at Monash and Melbourne Universities have determined the basic structure of one of the two known families of these deceptive proteins.
Using synchrotron light and working with a common virus that lives in people happily and for the most part harmlessly, they worked out the structure of the fake proteins. This is an important first step towards producing better vaccines and drugs to fight viral disease.
The research was posted online this week by the Journal of Biological Chemistry. It will appear in the September issue of the journal.
The paper describes the structure of m04 immunoevasin from mouse cytomegalovirus, a member of the m02 protein family.
Cytomegaloviruses belong to the herpesvirus family whose members can cause glandular fever, chicken pox and cold sores. About half the population become infected with the virus, develop flu-like illness and then carry the virus for life. But the virus can be dangerous to pregnant women and people whose immune system becomes supressed.
The mouse variant is an important model for understanding how this family of viruses can hide from our immune systems.
“Our work highlights how these viruses mimic the immune system in order to evade it,” says Monash University’s Dr Richard Berry, a senior author of the paper. He works in a research group led by Prof Jamie Rossjohn, the other senior author and a Chief Investigator of the Imaging Centre.
Mouse and human immune T-cells patrol our bodies checking on the health of cells. One of things they look for is a complex of proteins on the surface of cells. This major histocompatibility complex (MHC) presents a snapshot of what’s inside the cell. If bits of viral protein are detected by the T cells, they flag the infected cell for destruction.
Viruses fight back by disrupting the production of the MHC protein complex, thus reducing the numbers on the outer membrane.
But then, the next stage of what could be described as an evolutionary arms race kicks in. If there are too few MHC proteins on the outer membrane of a cell, then a different type of immune cell, termed the natural killer cell, will kill the cell just to be safe.
Cytomegaloviruses have responded to this by making large families of fake cellular proteins that interfere with natural killer cell recognition. It is the basic structure of one of these families that Rossjohn, Berry and their colleagues have become the first researchers to reveal.
“It’s been a race against our international competitors which we won with the help of the Australian Synchrotron,” Rossjohn says. “We were only able to produce very small protein crystals from which to solve the structures—too small to allow us to gain meaningful data with anything other than synchrotron X-rays.”
Abstract and paper available at: www.jbc.org/content/early/2014/06/30/jbc.M114.584128.full.pdf
More about the Imaging Centre at: www.imagingcoe.org
Richard Berry, senior author, firstname.lastname@example.org
Niall Byrne, +61 417 131 977, email@example.com (for the ARC Imaging Centre)
Lucy Handford, firstname.lastname@example.org (for Monash University)
Annie Rahilly, email@example.com (for the University of Melbourne)
The Structure of the Cytomegalovirus-Encoded m04 Glycoprotein, a Prototypical Member of the m02 Family of Immunoevasins
The ability of cytomegaloviruses (CMV) to evade the host’s immune system is dependent on the expression of a wide array of glycoproteins, many of which interfere with natural killer (NK) cell function. In murine CMV, two large protein families mediate this immune-evasive function. While it is established that the m145 family members mimic the structure of major histocompatibility complex (MHC)-I molecules, the structure of the m02 family remains unknown. The most extensively studied m02 family member is m04, a glycoprotein that escorts newly assembled MHC-I molecules to the cell surface, presumably to avoid missing-self recognition. Here we report the crystal structure of the m04 ectodomain, thereby providing insight into this large immunoevasin family. m04 adopted a β-sandwich immunoglobulin variable (Ig-V) like fold, despite sharing very little sequence identity with the Ig-V superfamily. In addition to the Ig-V core, m04 possesses several unique structural features that included an unusual β-strand topology, a number of extended loops and a prominent α-helix. The m04 interior was packed by a myriad of hydrophobic residues that form distinct clusters around two conserved tryptophan residues. This hydrophobic core was well conserved throughout the m02 family, thereby indicating that MCMV encodes a number of Ig-V like molecules. We show that m04 binds a range of MHC-I molecules with low affinity in a peptide-independent manner. Accordingly the structure of m04, which represents the first example of an MCMV encoded Ig-V fold, provides a basis for understanding the structure and function of this enigmatic and large family of immunoevasins.
Authors: Richard Berry1, Julian P. Vivian1, Felix A. Deuss1, Gautham R. Balaji1, Philippa M. Saunders2, Jie Lin2, Dene R. Littler1, Andrew G. Brooks2 and Jamie Rossjohn1
Author Affiliations: 1 Monash University, Australia; 2 Melbourne University, Australia
This work was supported by the Australian Research Council and the NHMRC of Australia.
About the Imaging Centre
The ARC Centre of Excellence for Advanced Molecular Imaging integrates physics, chemistry and biology to unravel the complex molecular interactions that define immunity. The Centre will develop new imaging methods to visualize atomic, molecular and cellular details of how immune proteins interact and effect immune responses.
It will enable Australia to be an international leader in biological imaging, train the next generation of interdisciplinary scientists, and provide new insights into combating common diseases that afflict society.
The highly collaborative Centre brings together biologists, physicists and chemists from five Australian universities, the University of Warwick in the UK, the Australian Nuclear Science and Technology Organisation (ANSTO), synchrotrons in Australia and Germany and several high-tech companies.
It is an Australian Research Council (ARC) Centre of Excellence and funded with more than $39 million over seven years from 2014—$28 million from the ARC and a further $10 million from its partners. The Centre’s Director is Prof James Whisstock of Monash University.
More at: www.imagingcoe.org
About Richard Berry
NHMRC Peter Doherty post-doctoral fellow in the Department of Biochemistry and Molecular Biology at Monash University and researcher in the Rossjohn Laboratory.
About Jamie Rossjohn
NHMRC Fellow in the Department of Biochemistry and Molecular Biology at Monash University and Chief Investigator at the ARC Centre for Advanced Molecular Imaging
His research is centred on understanding the basis of infection and immunity, specifically host recognition, responses developed by the pathogen and drug design to modulate and/or counteract these events.