P03138 (HBSAG_HBVD3) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Large envelope protein

Alternative name(s):
L glycoprotein
L-HBsAg
Short name=LHB
Large S protein
Large surface protein
Major surface antigen

Gene names

Name:

S

Organism

Hepatitis B virus genotype D subtype ayw (isolate France/Tiollais/1979) (HBV-D) [Complete proteome]

Taxonomic identifier

490133 [NCBI]

Taxonomic lineage

Viruses › Retro-transcribing viruses › Hepadnaviridae › Orthohepadnavirus

Virus host

Pan troglodytes (Chimpanzee) [TaxID: 9598]
Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	389 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	The large envelope protein exists in two topological conformations, one which is termed 'external' or Le-HBsAg and the other 'internal' or Li-HBsAg. In its external conformation the protein attaches the virus to cell receptors and thereby initiating infection. This interaction determines the species specificity and liver tropism. This attachment induces virion internalization predominantly through caveolin-mediated endocytosis. The large envelope protein also assumes fusion between virion membrane and endosomal membrane Probable. In its internal conformation the protein plays a role in virion morphogenesis and mediates the contact with the nucleocapsid like a matrix protein By similarity. Ref.7 Ref.10 The middle envelope protein plays an important role in the budding of the virion. It is involved in the induction of budding in a nucleocapsid independent way. In this process the majority of envelope proteins bud to form subviral lipoprotein particles of 22 nm of diameter that do not contain a nucleocapsid By similarity. Ref.7 Ref.10
Subunit structure	Li-HBsAg interacts with capsid protein and with HDV Large delta antigen. Isoform M associates with host chaperone CANX through its pre-S2 N glycan. This association may be essential for M proper secretion By similarity.
Subcellular location	Virion membrane By similarity.
Domain	The large envelope protein is synthesized with the pre-S region at the cytosolic side of the endoplasmic reticulum and, hence will be within the virion after budding. Therefore the pre-S region is not N-glycosylated. Later a post-translational translocation of N-terminal pre-S and TM1 domains occur in about 50% of proteins at the virion surface. These molecules change their topology by an unknown mechanism, resulting in exposure of pre-S region at virion surface. For isoform M in contrast, the pre-S2 region is translocated cotranslationally to the endoplasmic reticulum lumen and is N-glycosylated.
Post-translational modification	Isoform M is N-terminaly acetylated at a ratio of 90%, N- and O-glycosylated at the pre-S2 region. Ref.8 Ref.9 Myristoylated By similarity.
Biotechnological use	Systematic vaccination of individuals at risk of exposure to the virus has been the main method of controlling the morbidity and mortality associated with hepatitis B. The first hepatitis B vaccine was manufactured by the purification and inactivation of HBsAg obtained from the plasma of chronic hepatitis B virus carriers. The vaccine is now produced by recombinant DNA techniques and expression of the S isoform in yeast cells. The pre-S region do not seem to induce strong enough antigenic response.
Sequence similarities	Belongs to the orthohepadnavirus major surface antigen family.
Sequence caution	The sequence AAA45496.1 differs from that shown. Reason: Erroneous initiation. The sequence CAA26324.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	Caveolin-mediated endocytosis of virus by host Fusion of virus membrane with host endosomal membrane Fusion of virus membrane with host membrane Host-virus interaction Initiation of viral infection Viral attachment to host cell Viral penetration into host cytoplasm Virus endocytosis by host
Cellular component	Membrane Virion
Coding sequence diversity	Alternative initiation Alternative splicing
Domain	Transmembrane Transmembrane helix
PTM	Acetylation Glycoprotein Lipoprotein Myristate
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW viral reproduction Inferred from electronic annotation. Source: InterPro
Cellular component	integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW virion membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing and alternative initiation. [Align] [Select]

Isoform L (identifier: P03138-1)

Also known as: Large envelope protein; LHB; L-HBsAg;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform M (identifier: P03138-2)

Also known as: Middle envelope protein; MHB; M-HBsAg;

The sequence of this isoform differs from the canonical sequence as follows:
     1-108: Missing.

Isoform S (identifier: P03138-3)

Also known as: Small envelope protein; SHB; S-HBsAg;

The sequence of this isoform differs from the canonical sequence as follows:
     1-163: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed; by host By similarity
	Chain	2 – 389	388	Large envelope protein		PRO_0000038107
Regions
	Topological domain	2 – 242	241	Cytoplasmic; in internal conformation Potential
	Topological domain	2 – 170	169	Extracellular; in external conformation Potential
	Transmembrane	171 – 191	21	Helical; Note=In external conformation; Potential
	Topological domain	192 – 242	51	Cytoplasmic; in external conformation Potential
	Transmembrane	243 – 263	21	Helical; Potential
	Topological domain	264 – 337	74	Extracellular Potential
	Transmembrane	338 – 358	21	Helical; Potential
	Topological domain	359 – 364	6	Cytoplasmic Potential
	Transmembrane	365 – 387	23	Helical; Potential
	Topological domain	388 – 389	2	Extracellular Potential
	Region	2 – 163	162	Pre-S
	Region	2 – 108	107	Pre-S1
	Region	109 – 163	55	Pre-S2
Amino acid modifications
	Modified residue	109	1	N-acetylmethionine; by host; in isoform M; partial Ref.8
	Lipidation	2	1	N-myristoyl glycine; by host By similarity
	Glycosylation	112	1	N-linked (GlcNAc...); by host; in isoform M Ref.8
	Glycosylation	145	1	O-linked (GalNAc...); by host; in isoform M Ref.8 Ref.9
	Glycosylation	309	1	N-linked (GlcNAc...); by host By similarity
Natural variations
	Alternative sequence	1 – 163	163	Missing in isoform S.		VSP_031404
	Alternative sequence	1 – 108	108	Missing in isoform M.		VSP_031405
	Natural variant	75	1	Q → E in strain: Latvia.
	Natural variant	147	1	A → S in strain: Latvia.
	Natural variant	150	1	L → I in strain: Latvia.
	Natural variant	288 – 290	3	MTT → TTP in strain: Latvia.
Experimental info
	Mutagenesis	2	1	G → A: Complete loss of myristoylation. Complete loss of infectivity. Ref.6
	Mutagenesis	11 – 15	5	LGFFP → KL: Complete loss of infectivity. Ref.11
	Mutagenesis	11	1	L → R: Complete loss of infectivity. Ref.11
	Mutagenesis	12	1	G → E: Complete loss of infectivity. Ref.11
	Mutagenesis	13 – 14	2	FF → SS: Complete loss of infectivity.
	Mutagenesis	13	1	F → S: Complete loss of infectivity.
	Mutagenesis	16 – 20	5	DHQLD → KL: Complete loss of infectivity.
	Mutagenesis	21 – 25	5	PAFRA → KL: Complete loss of infectivity.
	Mutagenesis	26 – 30	5	NTANP → KL: Complete loss of infectivity.
	Mutagenesis	31 – 35	5	DWDFN → KL: Complete loss of infectivity.
	Mutagenesis	36 – 40	5	PNKDT → KL: Complete loss of infectivity.
	Mutagenesis	41 – 45	5	WPDAN → KL: Complete loss of infectivity.
	Mutagenesis	47 – 50	4	VGAG → L: Complete loss of infectivity.
	Mutagenesis	51 – 55	5	AFGLG → KL: Complete loss of infectivity.
	Mutagenesis	56 – 60	5	FTPPH → KL: Complete loss of infectivity.
	Mutagenesis	61 – 65	5	GGLLG → KL: Complete loss of infectivity.
	Mutagenesis	66 – 70	5	WSPQA → KL: Complete loss of infectivity.
	Mutagenesis	71 – 75	5	QGILQ → KL: Complete loss of infectivity.
	Mutagenesis	76 – 80	5	TLPAN → KL: No effect on infectivity.
	Mutagenesis	81 – 85	5	PPPAS → KL: No effect on infectivity.
	Mutagenesis	86 – 90	5	TNRQS → KL: No effect on infectivity.
	Mutagenesis	91 – 95	5	GRQPT → KL: No effect on infectivity.
	Mutagenesis	96 – 100	5	PLSPP → KL: No effect on infectivity.
	Mutagenesis	101 – 105	5	LRNTH → KL: No effect on infectivity. Ref.12
	Mutagenesis	106 – 110	5	PQAMQ → KL: No effect on infectivity. Ref.12

Sequences

	Sequence		Length	Mass (Da)
	Isoform L (Large envelope protein) (LHB) (L-HBsAg) [UniParc]. Last modified January 23, 2007. Version 3. Checksum: 6DC9E682DA694F63	FASTA	389	42,766
	10 20 30 40 50 60 MGQNLSTSNP LGFFPDHQLD PAFRANTANP DWDFNPNKDT WPDANKVGAG AFGLGFTPPH 70 80 90 100 110 120 GGLLGWSPQA QGILQTLPAN PPPASTNRQS GRQPTPLSPP LRNTHPQAMQ WNSTTFHQTL 130 140 150 160 170 180 QDPRVRGLYF PAGGSSSGTV NPVLTTASPL SSIFSRIGDP ALNMENITSG FLGPLLVLQA 190 200 210 220 230 240 GFFLLTRILT IPQSLDSWWT SLNFLGGTTV CLGQNSQSPT SNHSPTSCPP TCPGYRWMCL 250 260 270 280 290 300 RRFIIFLFIL LLCLIFLLVL LDYQGMLPVC PLIPGSSTTS TGPCRTCMTT AQGTSMYPSC 310 320 330 340 350 360 CCTKPSDGNC TCIPIPSSWA FGKFLWEWAS ARFSWLSLLV PFVQWFVGLS PTVWLSVIWM 370 380 MWYWGPSLYS ILSPFLPLLP IFFCLWVYI
	Isoform M (Middle envelope protein) (MHB) (M-HBsAg) [UniParc]. Checksum: 472F0BBD949E2E56	FASTA	281	31,283
	10 20 30 40 50 60 MQWNSTTFHQ TLQDPRVRGL YFPAGGSSSG TVNPVLTTAS PLSSIFSRIG DPALNMENIT 70 80 90 100 110 120 SGFLGPLLVL QAGFFLLTRI LTIPQSLDSW WTSLNFLGGT TVCLGQNSQS PTSNHSPTSC 130 140 150 160 170 180 PPTCPGYRWM CLRRFIIFLF ILLLCLIFLL VLLDYQGMLP VCPLIPGSST TSTGPCRTCM 190 200 210 220 230 240 TTAQGTSMYP SCCCTKPSDG NCTCIPIPSS WAFGKFLWEW ASARFSWLSL LVPFVQWFVG 250 260 270 280 LSPTVWLSVI WMMWYWGPSL YSILSPFLPL LPIFFCLWVY I
	Isoform S (Small envelope protein) (SHB) (S-HBsAg) [UniParc]. Checksum: FCFEAE391AB57B01	FASTA	226	25,421
	10 20 30 40 50 60 MENITSGFLG PLLVLQAGFF LLTRILTIPQ SLDSWWTSLN FLGGTTVCLG QNSQSPTSNH 70 80 90 100 110 120 SPTSCPPTCP GYRWMCLRRF IIFLFILLLC LIFLLVLLDY QGMLPVCPLI PGSSTTSTGP 130 140 150 160 170 180 CRTCMTTAQG TSMYPSCCCT KPSDGNCTCI PIPSSWAFGK FLWEWASARF SWLSLLVPFV 190 200 210 220 QWFVGLSPTV WLSVIWMMWY WGPSLYSILS PFLPLLPIFF CLWVYI

References

[1]	"Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in E. coli." Galibert F., Mandart E., Fitoussi F., Tiollais P., Charnay P. Nature 281:646-650(1979) [PubMed: 399327] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"Subtype ayw variant of hepatitis B virus. DNA primary structure analysis." Bichko V., Pushko P., Dreilina D., Pumpen P., Gren E.Y. FEBS Lett. 185:208-212(1985) [PubMed: 3996597] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Strain: Latvia.
[3]	"Synthesis of the full amino acid sequence of the surface antigen of the hepatitis B virus in Escherichia coli." Kozlovskaia T.M., Pumpen P.P., Borisova G.P., Dishler A.V., Bychko V.V. Dokl. Akad. Nauk SSSR 274:1250-1253(1984) [PubMed: 6373205] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Strain: Latvia.
[4]	"The preS1 protein of hepatitis B virus is acylated at its amino terminus with myristic acid." Persing D.H., Varmus H.E., Ganem D. J. Virol. 61:1672-1677(1987) [PubMed: 3573147] [Abstract] Cited for: MYRISTOYLATION AT GLY-2.
[5]	"Novel transmembrane topology of the hepatitis B virus envelope proteins." Prange R., Streeck R.E. EMBO J. 14:247-256(1995) [PubMed: 7835336] [Abstract] Cited for: TRANSMEMBRANE TOPOLOGY.
[6]	"Myristylation of the hepatitis B virus large surface protein is essential for viral infectivity." Gripon P., Le Seyec J., Rumin S., Guguen-Guillouzo C. Virology 213:292-299(1995) [PubMed: 7491754] [Abstract] Cited for: MUTAGENESIS OF GLY-2.
[7]	"Role for calnexin and N-linked glycosylation in the assembly and secretion of hepatitis B virus middle envelope protein particles." Werr M., Prange R. J. Virol. 72:778-782(1998) [PubMed: 9420286] [Abstract] Cited for: FUNCTION.
[8]	"Analysis of the pre-S2 N- and O-linked glycans of the M surface protein from human hepatitis B virus." Schmitt S., Glebe D., Alving K., Tolle T.K., Linder M., Geyer H., Linder D., Peter-Katalinic J., Gerlich W.H., Geyer R. J. Biol. Chem. 274:11945-11957(1999) [PubMed: 10207016] [Abstract] Cited for: GLYCOSYLATION AT ASN-112 AND THR-145, ACETYLATION AT MET-109. Strain: Isolate clinical.
[9]	"Structure of pre-S2 N- and O-linked glycans in surface proteins from different genotypes of hepatitis B virus." Schmitt S., Glebe D., Tolle T.K., Lochnit G., Linder D., Geyer R., Gerlich W.H. J. Gen. Virol. 85:2045-2053(2004) [PubMed: 15218190] [Abstract] Cited for: GLYCOSYLATION AT THR-145.
[10]	"Analysis of the cytosolic domains of the hepatitis B virus envelope proteins for their function in viral particle assembly and infectivity." Blanchet M., Sureau C. J. Virol. 80:11935-11945(2006) [PubMed: 17020942] [Abstract] Cited for: FUNCTION.
[11]	"Characterization of a hepatitis B and hepatitis delta virus receptor binding site." Engelke M., Mills K., Seitz S., Simon P., Gripon P., Schnolzer M., Urban S. Hepatology 43:750-760(2006) [PubMed: 16557545] [Abstract] Cited for: MUTAGENESIS OF LEU-11; GLY-12 AND 13-PHE-PHE-14.
[12]	"Infectivity determinants of the hepatitis B virus pre-S domain are confined to the N-terminal 75 amino acid residues." Blanchet M., Sureau C. J. Virol. 81:5841-5849(2007) [PubMed: 17376925] [Abstract] Cited for: MUTAGENESIS OF 11-LEU--PRO-15; 16-ASP--ASP-20; 21-PRO--ALA-25; 26-ASN--PRO-30; 31-ASP--ASN-35; 36-PRO--THR-40; 41-TRP--ASN-45; 46-LYS--GLY-50; 51-ALA--GLY-55; 56-PHE--HIS-60; 61-GLY--GLY-65; 66-TRP--ALA-70; 71-GLN--GLN-75; 76-THR--ASN-80; 81-PRO--SER-85; 86-THR--SER-90; 91-GLY--THR-95; 96-PRO--PRO-100; 101-LEU--HIS-105 AND 106-PRO--GLN-110.
[13]	"Functions of the large hepatitis B virus surface protein in viral particle morphogenesis." Bruss V., Gerhardt E., Vieluf K., Wunderlich G. Intervirology 39:23-31(1996) [PubMed: 8957666] [Abstract] Cited for: REVIEW.
[14]	"Role of glycan processing in hepatitis B virus envelope protein trafficking." Block T.M., Lu X., Mehta A., Park J., Blumberg B.S., Dwek R. Adv. Exp. Med. Biol. 435:207-216(1998) [PubMed: 9498079] [Abstract] Cited for: REVIEW.
[15]	"Envelopment of the hepatitis B virus nucleocapsid." Bruss V. Virus Res. 106:199-209(2004) [PubMed: 15567498] [Abstract] Cited for: REVIEW.
[16]	"Hepatitis B virus pre-S mutants, endoplasmic reticulum stress and hepatocarcinogenesis." Wang H.C., Huang W., Lai M.D., Su I.J. Cancer Sci. 97:683-688(2006) [PubMed: 16863502] [Abstract] Cited for: REVIEW.

Web resources

HepSEQ

Hepatitis virus B database

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

V01460 Genomic DNA. No translation available.
X02496 Genomic DNA. Translation: CAA26324.1. Different initiation.
M12393 Genomic DNA. Translation: AAA45496.1. Different initiation.

PIR

SAVLAH. A03703.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1A7L	X-ray	2.90	A/B/C	-	[»]
1IUD	X-ray	2.70	A	-	[»]

ModBase

Search...

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Family and domain databases

InterPro

IPR000349. Hepvir_surfAg.
[Graphical view]

Pfam

PF00695. vMSA. 1 hit.
[Graphical view]

ProtoNet

Search...

Entry information

Entry name

HBSAG_HBVD3

Accession

Primary (citable) accession number: P03138

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	January 23, 2007
Last modified:	May 31, 2011
This is version 70 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Viral Protein Annotation Program