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Protein

Calcium homeostasis modulator protein 1

Gene

CALHM1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Pore-forming subunit of a voltage-gated ion channel required for sensory perception of sweet, bitter and umami tastes. Specifically present in type II taste bud cells, where it plays a central role in sweet, bitter and umami taste perception by inducing ATP release from the cell, ATP acting as a neurotransmitter to activate afferent neural gustatory pathways. Acts both as a voltage-gated and calcium-activated ion channel: mediates neuronal excitability in response to changes in extracellular Ca2+ concentration. Has poor ion selectivity and forms a wide pore (around 14 Angstroms) that mediates permeation of Ca2+, Na+ and K+, as well as permeation of monovalent anions. Acts as an activator of the ERK1 and ERK2 cascade. Triggers endoplasmic reticulum stress by reducing the calcium content of the endoplasmic reticulum. May indirectly control amyloid precursor protein (APP) proteolysis and aggregated amyloid-beta (Abeta) peptides levels in a Ca2+ dependent manner.5 Publications

Enzyme regulationi

Inhibited by Gd3+, Ruthenium Red, and Zn2+ and partially inhibited by 2-aminoethoxydiphenyl borate.1 Publication

GO - Molecular functioni

  • calcium activated cation channel activity Source: UniProtKB
  • identical protein binding Source: IntAct
  • voltage-gated calcium channel activity Source: Ensembl
  • voltage-gated ion channel activity Source: UniProtKB

GO - Biological processi

  • ATP transport Source: UniProtKB
  • cation transport Source: UniProtKB
  • protein homooligomerization Source: UniProtKB
  • regulation of ion transmembrane transport Source: UniProtKB
  • sensory perception of bitter taste Source: UniProtKB
  • sensory perception of sweet taste Source: UniProtKB
  • sensory perception of umami taste Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Calcium channel, Ion channel

Keywords - Biological processi

Calcium transport, Ion transport, Transport

Keywords - Ligandi

Calcium

Protein family/group databases

TCDBi1.A.84.1.1. the calcium homeostasis modulator ca(2+) channel (calhm-c) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Calcium homeostasis modulator protein 1
Alternative name(s):
Protein FAM26C
Gene namesi
Name:CALHM1
Synonyms:FAM26C
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 10

Organism-specific databases

HGNCiHGNC:23494. CALHM1.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 1717CytoplasmicSequence analysisAdd
BLAST
Transmembranei18 – 3821HelicalSequence analysisAdd
BLAST
Topological domaini39 – 5012ExtracellularSequence analysisAdd
BLAST
Transmembranei51 – 7121HelicalSequence analysisAdd
BLAST
Topological domaini72 – 10837CytoplasmicSequence analysisAdd
BLAST
Transmembranei109 – 12921HelicalSequence analysisAdd
BLAST
Topological domaini130 – 18152ExtracellularSequence analysisAdd
BLAST
Transmembranei182 – 20221HelicalSequence analysisAdd
BLAST
Topological domaini203 – 346144CytoplasmicSequence analysisAdd
BLAST

GO - Cellular componenti

  • endoplasmic reticulum membrane Source: UniProtKB-SubCell
  • integral component of plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Endoplasmic reticulum, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi72 – 721N → G: Significant inhibition on the control of cytosolic Ca(2+) levels. Does not affect ion channel activity. 2 Publications
Mutagenesisi74 – 741N → A: Has no effect on glycosylation. 1 Publication
Mutagenesisi114 – 1141W → A: Impairs ability to activate the ERK1 and ERK2 cascade. 1 Publication
Mutagenesisi121 – 1211D → C: Impaired ion channel activity in response to change in extracellular Ca(2+) concentration. 1 Publication
Mutagenesisi121 – 1211D → E: No effect. 1 Publication
Mutagenesisi140 – 1401N → A: Prevents glycosylation and impairs ability to activate the ERK1 and ERK2 cascade. 2 Publications
Mutagenesisi163 – 1631E → A: No effect. 1 Publication
Mutagenesisi166 – 1661D → R: No effect. 1 Publication

Organism-specific databases

PharmGKBiPA162380954.

Polymorphism and mutation databases

BioMutaiCALHM1.
DMDMi68565595.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 346346Calcium homeostasis modulator protein 1PRO_0000186723Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi140 – 1401N-linked (GlcNAc...)1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei74 – 741Not glycosylated

Keywords - PTMi

Glycoprotein

Proteomic databases

PaxDbiQ8IU99.
PRIDEiQ8IU99.

Expressioni

Tissue specificityi

Predominantly expressed in adult brain. Detected also in retinoic acid-differentiated SH-SY5Y cells. Specifically expressed in circumvallate taste bud cells.2 Publications

Gene expression databases

BgeeiQ8IU99.
CleanExiHS_CALHM1.
GenevisibleiQ8IU99. HS.

Organism-specific databases

HPAiHPA018317.

Interactioni

Subunit structurei

Homohexamer.2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself3EBI-1790341,EBI-1790341

GO - Molecular functioni

  • identical protein binding Source: IntAct

Protein-protein interaction databases

STRINGi9606.ENSP00000329926.

Structurei

3D structure databases

ProteinModelPortaliQ8IU99.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the FAM26 family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IG7G. Eukaryota.
ENOG410YNIM. LUCA.
GeneTreeiENSGT00530000062796.
HOGENOMiHOG000111295.
HOVERGENiHBG096020.
InParanoidiQ8IU99.
KOiK19738.
OMAiMNNNVSM.
OrthoDBiEOG70GMG1.
PhylomeDBiQ8IU99.
TreeFamiTF329085.

Family and domain databases

InterProiIPR029568. CALHM1.
IPR029569. FAM26.
[Graphical view]
PANTHERiPTHR32261. PTHR32261. 2 hits.
PTHR32261:SF2. PTHR32261:SF2. 2 hits.
PfamiPF14798. Ca_hom_mod. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q8IU99-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MMDKFRMIFQ FLQSNQESFM NGICGIMALA SAQMYSAFDF NCPCLPGYNA
60 70 80 90 100
AYSAGILLAP PLVLFLLGLV MNNNVSMLAE EWKRPLGRRA KDPAVLRYMF
110 120 130 140 150
CSMAQRALIA PVVWVAVTLL DGKCFLCAFC TAVPVSALGN GSLAPGLPAP
160 170 180 190 200
ELARLLARVP CPEIYDGDWL LAREVAVRYL RCISQALGWS FVLLTTLLAF
210 220 230 240 250
VVRSVRPCFT QAAFLKSKYW SHYIDIERKL FDETCTEHAK AFAKVCIQQF
260 270 280 290 300
FEAMNHDLEL GHTHGTLATA PASAAAPTTP DGAEEEREKL RGITDQGTMN
310 320 330 340
RLLTSWHKCK PPLRLGQEEP PLMGNGWAGG GPRPPRKEVA TYFSKV
Length:346
Mass (Da):38,264
Last modified:July 5, 2005 - v2
Checksum:i13A1FBA6592A9EC1
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti264 – 2641H → N in AAH36193 (PubMed:15489334).Curated
Sequence conflicti264 – 2641H → N in AAH36208 (PubMed:15489334).Curated

Polymorphismi

Leu-86 causes a dysregulation of Ca2+ homeostasis and amyloid precursor protein (APP) metabolism and has been suggested to be a risk factor for the development of Alzheimer disease (PubMed:18585350, PubMed:20061624, PubMed:20164592). However, this association with Alzheimer disease could not be confirmed in a number of studies performed in different populations (PubMed:19472444, PubMed:19070563, PubMed:19191331, PubMed:19191332, PubMed:19545933, PubMed:19655363, PubMed:21378601). According to a meta-analysis study, Leu-86 is likely not a genetic determinant of Alzheimer disease but may modulate age of onset by interacting with the effect of the APOE*4 allele of the APOE gene (PubMed:20847397).11 Publications

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti86 – 861L → P.12 Publications
Corresponds to variant rs2986017 [ dbSNP | Ensembl ].
VAR_023095

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AL139339 Genomic DNA. Translation: CAH71484.1.
BC036193 mRNA. Translation: AAH36193.1.
BC036208 mRNA. Translation: AAH36208.1.
CCDSiCCDS7550.1.
RefSeqiNP_001001412.3. NM_001001412.3.
UniGeneiHs.680365.

Genome annotation databases

EnsembliENST00000329905; ENSP00000329926; ENSG00000185933.
GeneIDi255022.
KEGGihsa:255022.
UCSCiuc001kxe.3. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AL139339 Genomic DNA. Translation: CAH71484.1.
BC036193 mRNA. Translation: AAH36193.1.
BC036208 mRNA. Translation: AAH36208.1.
CCDSiCCDS7550.1.
RefSeqiNP_001001412.3. NM_001001412.3.
UniGeneiHs.680365.

3D structure databases

ProteinModelPortaliQ8IU99.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9606.ENSP00000329926.

Protein family/group databases

TCDBi1.A.84.1.1. the calcium homeostasis modulator ca(2+) channel (calhm-c) family.

Polymorphism and mutation databases

BioMutaiCALHM1.
DMDMi68565595.

Proteomic databases

PaxDbiQ8IU99.
PRIDEiQ8IU99.

Protocols and materials databases

DNASUi255022.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000329905; ENSP00000329926; ENSG00000185933.
GeneIDi255022.
KEGGihsa:255022.
UCSCiuc001kxe.3. human.

Organism-specific databases

CTDi255022.
GeneCardsiCALHM1.
H-InvDBHIX0201512.
HGNCiHGNC:23494. CALHM1.
HPAiHPA018317.
MIMi612234. gene.
neXtProtiNX_Q8IU99.
PharmGKBiPA162380954.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IG7G. Eukaryota.
ENOG410YNIM. LUCA.
GeneTreeiENSGT00530000062796.
HOGENOMiHOG000111295.
HOVERGENiHBG096020.
InParanoidiQ8IU99.
KOiK19738.
OMAiMNNNVSM.
OrthoDBiEOG70GMG1.
PhylomeDBiQ8IU99.
TreeFamiTF329085.

Miscellaneous databases

GenomeRNAii255022.
NextBioi92439.
PROiQ8IU99.
SOURCEiSearch...

Gene expression databases

BgeeiQ8IU99.
CleanExiHS_CALHM1.
GenevisibleiQ8IU99. HS.

Family and domain databases

InterProiIPR029568. CALHM1.
IPR029569. FAM26.
[Graphical view]
PANTHERiPTHR32261. PTHR32261. 2 hits.
PTHR32261:SF2. PTHR32261:SF2. 2 hits.
PfamiPF14798. Ca_hom_mod. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "The DNA sequence and comparative analysis of human chromosome 10."
    Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J.
    , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.
    Nature 429:375-381(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT PRO-86.
    Tissue: Brain.
  3. Cited for: FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, GLYCOSYLATION AT ASN-140, VARIANT PRO-86, POLYMORPHISM, MUTAGENESIS OF ASN-72; ASN-74 AND ASN-140.
  4. "Expression of genes encoding multi-transmembrane proteins in specific primate taste cell populations."
    Moyer B.D., Hevezi P., Gao N., Lu M., Kalabat D., Soto H., Echeverri F., Laita B., Yeh S.A., Zoller M., Zlotnik A.
    PLoS ONE 4:E7682-E7682(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY.
  5. "Calcium homoeostasis modulator 1 (CALHM1) reduces the calcium content of the endoplasmic reticulum (ER) and triggers ER stress."
    Gallego-Sandin S., Alonso M.T., Garcia-Sancho J.
    Biochem. J. 437:469-475(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  6. "Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability."
    Ma Z., Siebert A.P., Cheung K.H., Lee R.J., Johnson B., Cohen A.S., Vingtdeux V., Marambaud P., Foskett J.K.
    Proc. Natl. Acad. Sci. U.S.A. 109:E1963-E1971(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION, MUTAGENESIS OF ASN-72; ASP-121; GLU-163 AND ASP-166.
  7. "Structural and functional similarities of calcium homeostasis modulator 1 (CALHM1) ion channel with connexins, pannexins, and innexins."
    Siebert A.P., Ma Z., Grevet J.D., Demuro A., Parker I., Foskett J.K.
    J. Biol. Chem. 288:6140-6153(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBUNIT, TOPOLOGY, SUBCELLULAR LOCATION.
  8. "CALHM1 controls Ca2+-dependent MEK/ERK/RSK/MSK signaling in neurons."
    Dreses-Werringloer U., Vingtdeux V., Zhao H., Chandakkar P., Davies P., Marambaud P.
    J. Cell Sci. 126:1199-1206(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF TRP-114 AND ASN-140.
  9. "CALHM1 polymorphism is not associated with late-onset Alzheimer disease."
    Beecham G.W., Schnetz-Boutaud N., Haines J.L., Pericak-Vance M.A.
    Ann. Hum. Genet. 73:379-381(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT PRO-86.
  10. Cited for: VARIANT PRO-86.
  11. "No association between CALHM1 variation and risk of Alzheimer disease."
    Minster R.L., Demirci F.Y., DeKosky S.T., Kamboh M.I.
    Hum. Mutat. 30:E566-E569(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT PRO-86.
  12. "No association between CALHM1 and risk for Alzheimer dementia in a Belgian population."
    Sleegers K., Brouwers N., Bettens K., Engelborghs S., van Miegroet H., De Deyn P.P., Van Broeckhoven C.
    Hum. Mutat. 30:E570-E574(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT PRO-86.
  13. "CALHM1 variant is not associated with Alzheimer's disease among Asians."
    Tan E.K., Ho P., Cheng S.Y., Yih Y., Li H.H., Fook-Chong S., Lee W.L., Zhao Y.
    Neurobiol. Aging 32:546.E11-546.E12(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT PRO-86.
  14. "The P86L common allele of CALHM1 does not influence risk for Alzheimer disease in Japanese cohorts."
    Inoue K., Tanaka N., Yamashita F., Sawano Y., Asada T., Goto Y.
    Am. J. Med. Genet. B Neuropsychiatr. Genet. 153:532-535(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT PRO-86.
  15. "CALHM1 P86L polymorphism is a risk factor for Alzheimer's disease in the Chinese population."
    Cui P.J., Zheng L., Cao L., Wang Y., Deng Y.L., Wang G., Xu W., Tang H.D., Ma J.F., Zhang T., Ding J.Q., Cheng Q., Chen S.D.
    J. Alzheimers Dis. 19:31-35(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT PRO-86.
  16. Cited for: VARIANT PRO-86.
  17. "The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study."
    Lambert J.C., Sleegers K., Gonzalez-Perez A., Ingelsson M., Beecham G.W., Hiltunen M., Combarros O., Bullido M.J., Brouwers N., Bettens K., Berr C., Pasquier F., Richard F., Dekosky S.T., Hannequin D., Haines J.L., Tognoni G., Fievet N.
    , Dartigues J.F., Tzourio C., Engelborghs S., Arosio B., Coto E., De Deyn P., Del Zompo M., Mateo I., Boada M., Antunez C., Lopez-Arrieta J., Epelbaum J., Schjeide B.M., Frank-Garcia A., Giedraitis V., Helisalmi S., Porcellini E., Pilotto A., Forti P., Ferri R., Delepine M., Zelenika D., Lathrop M., Scarpini E., Siciliano G., Solfrizzi V., Sorbi S., Spalletta G., Ravaglia G., Valdivieso F., Vepsalainen S., Alvarez V., Bosco P., Mancuso M., Panza F., Nacmias B., Bossu P., Hanon O., Piccardi P., Annoni G., Mann D., Marambaud P., Seripa D., Galimberti D., Tanzi R.E., Bertram L., Lendon C., Lannfelt L., Licastro F., Campion D., Pericak-Vance M.A., Soininen H., Van Broeckhoven C., Alperovitch A., Ruiz A., Kamboh M.I., Amouyel P.
    J. Alzheimers Dis. 22:247-255(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT PRO-86.
  18. "No association between CALHM1 polymorphism and Alzheimer's disease risk in a Hungarian population."
    Feher A., Juhasz A., Rimanoczy A., Pakaski M., Kalman J., Janka Z.
    Psychiatr. Genet. 21:249-252(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT PRO-86.

Entry informationi

Entry nameiCAHM1_HUMAN
AccessioniPrimary (citable) accession number: Q8IU99
Secondary accession number(s): Q5W091
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 5, 2005
Last sequence update: July 5, 2005
Last modified: March 16, 2016
This is version 105 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 10
    Human chromosome 10: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.