CRYSTAL STRUCTURE OF NEWCASTLE DISEASE

4G1G: Crystal Structure of Newcastle Disease Virus Matrix Protein



4G1G: Crystal Structure of Newcastle Disease Virus Matrix Protein

Introduction

Newcastle disease virus (NDV) belongs to the large and diverse family of paramyxoviruses, which is responsible for many human and animal diseases. The paramyxoviruses include other viruses such as mumps virus, measles virus, Sendai virus, respiratory syncytial virus (RSV), metapneumovirus (MPV), parainfluenza viruses (PIV) 1-5, Nipah virus and Hendra virus. NDV infects birds and many different strains have been isolated worldwide that vary in pathogenicity and virulence. Highly virulent strains can cause a contagious disease with respiratory, neurological and digestive tract pathology, with the most severe infections leading to substantial economic losses in the poultry industry, despite aggressive vaccination programs (Biacchesi & Skiadopoulos, 2004).

Highly virulent velogenic viscerotropic NDV strains, known as exotic NDV (END) strains, not endemic in the US, have caused severe disease outbreaks, such as the 1971 outbreak that required the killing of over 12 million chickens at a cost of $56 million with additional costs over a 4 year cleanup. A more recent END outbreak in 2002-2003 required the culling of over 3 million chickens in California at a cost of over $161 million. Continuing concerns about the severe economic impact of NDV outbreaks has led to the classification of NDV strains with an intracerebral pathogenicity index of >0.7, or containing a fusion protein with a multi-basic cleavage site, as a U.S. Department of Agriculture Select Agent , . Recently it has been shown that NDV is able to selectively kill tumor cells, suggesting it could be useful as an oncolytic agent, and NDV is also being investigated as a potential vaccine vector (reviewed in ).

Discussion

Paramyxoviruses are enveloped, negative-sense, single-stranded RNA viruses. Virions consist of a nucleocapsid, a matrix protein, and an envelope formed by a lipid membrane, typically with two glycoproteins displayed on the surface. For virus penetration into target cells, the lipid envelope must fuse with a cell membrane. Membrane fusion, for nearly all paramyxoviruses, is triggered at the cell surface in a receptor-dependent, pH-independent manner, unlike the pH-dependent influenza virus hemagglutinin mechanism. For most members of the virus family, two viral glycoproteins are required to mediate this entry process - the fusion (F) glycoprotein and an attachment protein referred to as hemagglutinin-neuraminidase (HN), hemagglutinin (H), or glycoprotein (G), depending on the virus. Activation of the F protein requires virus-specific (homotypic) interactions with the attachment glycoprotein for viral entry, except for RSV and MPV (Lamb & Jardetzky, 2007).

The HN attachment proteins are found in a subset of the paramyxoviruses, including NDV, mumps virus, parainfluenza virus 5 (PIV5), Sendai virus, and human parainfluenza viruses 1-4 (hPIV1-4) . HN protein binds to the receptor (sialic acid) for virus attachment to cells and plays additional roles in the virus life cycle including F activation, and receptor-destroying (neuraminidase) activity to facilitate virus budding. HNs are type II membrane proteins, with N-terminal transmembrane domains followed by a stalk region and a large C-terminal globular head ...