4wzn
From Proteopedia
CRYSTAL STRUCTURE OF THE 2B PROTEIN SOLUBLE DOMAIN FROM HEPATITIS A VIRUS
Structural highlights
FunctionPOLG_HAVHM Capsid proteins VP1, VP2, and VP3 form a closed capsid enclosing the viral positive strand RNA genome. All these proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The capsid interacts with HAVCR1 to provide virion attachment to target cell (By similarity). Protein VP0: VP0 precursor is a component of immature procapsids. The N-terminal domain of VP0, protein VP4, is needed for the assembly of 12 pentamers into the icosahedral structure. Unlike other picornaviruses, HAV VP4 does not seem to be myristoylated and has not been detected in mature virions, supposedly owing to its small size. VP1-2A precursor is a component of immature procapsids and corresponds to an extended form of the structural protein VP1. The C-terminal domain of VP1-2A, protein 2A, acts as an assembly signal that allows pentamerization of P1-2A, which is the precursor of the structural proteins. 2A is proteolytically removed from particulate VP1-2A by a host protease and does not seem to be found in mature particles. Protein 2B and 2BC precursor affect membrane integrity and cause an increase in membrane permeability. Protein 2C: Associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities (By similarity). Protein 3A, via its hydrophobic domain, serves as membrane anchor to the 3AB and 3ABC precursors. The 3AB precursor interacts with the 3CD precursor and with RNA structures found at both the 5'- and 3'-termini of the viral genome. Since the 3AB precursor contains the hydrophobic domain 3A, it probably anchors the whole viral replicase complex to intracellular membranes on which viral RNA synthesis occurs. The 3ABC precursor is targeted to the mitochondrial membrane where protease 3C activity cleaves and inhibits the host antiviral protein MAVS, thereby disrupting activation of IRF3 through the IFIH1/MDA5 pathway. In vivo, the protease activity of 3ABC precursor is more efficient in cleaving the 2BC precursor than that of protein 3C. The 3ABC precursor may therefore play a role in the proteolytic processing of the polyprotein. Protein 3B is covalently linked to the 5'-end of both the positive-strand and negative-strand genomic RNAs. It acts as a genome-linked replication primer. Protease 3C: cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind cooperatively to the protease. Also cleaves host proteins such as PCBP2. RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals. Publication Abstract from PubMedThe complexity of viral RNA synthesis and the numerous participating factors require a mechanism to topologically coordinate and concentrate these multiple viral and cellular components, ensuring a concerted function. Similar to all other positive-strand RNA viruses, picornaviruses induce rearrangements of host intracellular membranes to create structures, which act as functional scaffolds for genome replication. The membrane-targeting proteins 2B, 2C, their precursor 2BC, and protein 3A appear primarily involved in membrane remodeling. Little is known about the structure of these proteins and the mechanisms by which they induce massive membrane remodeling. Here we report the crystal structure of the soluble region of hepatitis A virus (HAV) protein 2B, consisting of two domains: a C-terminal helical bundle, preceded by a N-terminal curved five-stranded anti-parallel beta-sheet that displays striking structural similarity to the beta-barrel domain of enteroviral 2A proteins. Moreover, the helicoidal arrangement of the protein molecules in the crystal provides a model for 2B-induced host membrane remodeling during HAV infection. IMPORTANCE: No structural information is currently available for the 2B protein of any picornavirus, despite being involved in a critical process in viral factories formation: the rearrangement of host intracellular membranes. Here we present the structure of the soluble domain of the 2B protein of HepatititsA virus (HAV). Its arrangement, both in crystals and in solution under physiological conditions can help to understand its function and sheds some light on the membrane rearrangement process, a putative target of future antiviral drugs. Moreover, this first structure of a picornaviral2B protein also unveils a closer evolutionary relationship between the hepatovirus and enterovirus genres within the Picornaviridae family. Structural Basis for Host Membrane Remodeling Induced by Protein 2B of Hepatitis A Virus.,Vives-Adrian L, Garriga D, Buxaderas M, Fraga JS, Barbosa Pereira PJ, Macedo-Ribeiroand S, Verdaguer N J Virol. 2015 Jan 14. pii: JVI.02881-14. PMID:25589659[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
