PROSITE documentation PDOC52105

Hantaviridae family large (L) protein endonuclease (ENDO) domain and cap binding domain (CBD) profiles

The Hantaviridae are a family of segmented negative-sense RNA viruses (sNSV) from the larger class of the Bunyaviricetes. There are several types of hantaviruses, some are non-pathogenic and some are pathogenic that cause serious illnesses in humans. These illnesses include hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). Hantaviruses of different types are distributed across various regions worldwide; they can also be classified as Old World and New World Hantaviruses. The old world viruses such as the Hantaan virus, Seoul virus, and Dobrava-Belgrade virus causes HFRS diseases. The HCPS disease occurs due to New World hantaviruses such as the Sin Nombre [1,2,3,4,5,6].

Hantaviridae have three genome segments termed the small (S), medium (M), and large (L). The S and M segments encode the viral nucleoprotein and surface glycoproteins Gn/Gc, respectively. The L segment encodes the L protein, an approximately 250 kDa polymerase. The polymerase is a multifunctional enzyme that contains an N-terminal His+ endonuclease (ENDO), a RNA-dependent RNA polymerase (RdRp) (see <PDOC50507>), and a presumed cap binding domain (CBD) at the C-terminus. The endonuclease and cap-binding functions are required for viral transcription initiation via cap-snatching to provide short, capped RNA primers derived from host cell mRNAs. Cap-snatching involves two steps. First, the 5' end of a cellular mRNA is bound by the CBD and secondly, the cap is cleaved off several nucleotides downstream by the ENDO. The capped RNA fragment is used as a primer to initiate transcription of the viral mRNA by the RdRp [1,2,3,4,5,6].

The ENDO domain consists of two lobes, with the conserved active site buried within a cavity between them (see <PDB:5IZE>). One lobe consists of a central β-sheet surrounded by a long α-helix and several short helices, and the other lobe is mainly composed of a helix bundle. The ENDO domain is a metal ion-dependent nuclease and harbors a highly conserved H-PD-D/E-K catalytic motif. The ENDO domain active site contains two divalent manganese metal ions which are catalytically active. One of the Mn(2+) ions is coordinated by His, Asp, Glu, and Val residues, and the second Mn(2+) ion is coordinated by Glu and Asp of the active site residues [1,2,4,5].

The CBD consists in a central five-stranded β-sheet containing a small β-hairpin insertion between the first and the second strand. A long α-helix packs against the central β-sheet. Extended from the CBD is a short four stranded β-sheet. The capability of CBD to bind capped RNA has been related to the length of the β-hairpin insertion (see <PDB:8QGU>) [2,6].

The profiles we developed cover the entire Hantaviridae L protein endonuclease and CBD domains.