---------------------------------------------------------------------------- UniProt - Swiss-Prot Protein Knowledgebase SIB Swiss Institute of Bioinformatics; Geneva, Switzerland European Bioinformatics Institute (EBI); Hinxton, United Kingdom Protein Information Resource (PIR); Washington DC, USA ---------------------------------------------------------------------------- Description: Metallothioneins: classification and list of entries Name: metallo.txt Release: 2024_02 of 27-Mar-2024 ---------------------------------------------------------------------------- This document provides both a brief description of the classification of metallothioneins into families as developed by Pierre-Alain Binz and Jeremias H.R. Kagi as well as the list, classified by family, of the metallothionein entries in UniProtKB/Swiss-Prot. The definition of the metallothionein superfamily and its subdivisions is presented at the bottom of this file. The description of the criteria characterising all families and subfamilies is to be found at: http://www.bioc.unizh.ch/mtpage/MT.html ======================== Metallothionein families ======================== Introduction ------------ Metallothioneins (MTs) constitute a superfamily of low molecular weight cysteine-rich metalloproteins and metallopeptides responsible for regulating the intracellular supply of the biologically essential zinc and copper ions and for protecting cells from the deleterious effects of exposure to elevated amounts of these and non-essential polarizable transition and posttransition metal ions such as Cd2+, Hg2+ and others. Since its discovery as a cadmium and zinc containing protein in horse kidney by Margoshes and Vallee [1] MT has been an object of intensive study in various branches of the life sciences [2,3]. MT is now known to occur in all animal phyla examined so far as well as in certain fungi, plants and cyanobacteria. In mammals, 20 totally conserved cysteine residues (Cys) bind, in the reduced form, a complement of 7 equivalents of polarizable bivalent metal ions giving rise to two unique metal-thiolate clusters with characteristic spectroscopic features [4]. The spontaneous refolding of the native structure upon metal addition attests to a guiding role of the positions of the Cys and other AAs conserved in the polypeptide chain. The invertebrate holo-MTs studied thusfar display similar clusters with structural and compositional variations due to different numbers and relative positions of the Cys residues on the polypeptide chain. An empirical classification into three classes was proposed by Fowler et al. [5] and Kojima [6]. Members of Class I are defined to include polypeptides related in the positions of the Cys to equine MT-1B while those of class II display none or very distant correspondence in this respect. Class I subsumes besides the vertebrate MTs all presently known crustacean and molluscan sequences. Class III MTs are polyisopeptides composed of atypical gamma- glutamylcysteinyl units and are no therefore direct gene products [5]. Since this classification system does not allow to differentiate clearly patterns of structural similarities we have now grouped all proteinaceous MT sequences (Class I and Class II) into families of phylogenetically related and, accordingly, alignable sequences. The subclassification discriminating subfamilies and subgroups of MT sequences is based on phylogenetic analyses inferred from both amino-acid and polynucleotide sequences [7-9]. The web page containing all details of the classification system, including strategy and results is to be found at: http://www.bioc.uzh.ch/mtpage/MT.html References ---------- [1] Margoshes M., Vallee B.L. A cadmium protein from equine kidney cortex. J. Am. Chem. Soc. 79:4813-4814(1957). [2] Kagi J.H.R. Overview of Metallothioneins. Methods Enzymol. 205:613-626(1991). [3] Kagi J.H.R., Kojima Y. Chemistry and biochemistry of metallothionein. Experientia Suppl. 52:25-61(1987). [4] Kagi J.H.R., Schaffer A. Biochemistry of metallothionein. Biochemistry 27:8509-8515(1988). [5] Fowler B.A., Hildebrand C.E., Kojima Y., Webb M. Nomenclature of metallothionein. Experientia Suppl. 52:21(1987). [6] Kojima Y. Definitions and nomenclature of metallothioneins. Methods Enzymol. 205:8-10(1991). [7] Binz P.-A. Metallothioneins: studies on molecular evolution and on the structural and chiroptical features of their metal thiolate clusters. PhD thesis, University Zurich, Switzerland (1996). [8] Kojima Y., Binz P.-A., Kagi J.H.R. Nomenclature of metallothionein: proposal for a revision. (In) Metallothionein IV, Klaassen C. (Ed.), pp3-6, Birkhauser Verlag, Basel, (1999). [9] Binz P.-A., Kagi J.H.R. Metallothionein: molecular evolution and classification. (In) Metallothionein IV, Klaassen C. (Ed.), pp7-13, Birkhauser Verlag, Basel, (1999). ------------------------------------------------------------------------------ ============================================= Swiss-Prot entries for metallothioneins (MTs) ============================================= Notes: Subdiv. = subdivision Subdivisions are described for each family Rem. = remarks: v: variant(s) known c: conflict(s) known p: partial sequence Source = molecular source: AA: protein sequence NA: nucleic acid sequence The criteria used for the classifications are described at the bottom of this document. ======================== Family 1: vertebrate MTs ======================== Pattern: K-x(1,2)-C-C-x-C-C-P-x(2)-C 3D structure status: available for mouse Cd7-MT-1 (PDB: 1DFS, 1DFT) human Cd7-MT-2 (PDB: 1HMU, 2HMU) rabbit Cd7-MT-2 (PDB: 1MRB, 2MRB) rat Cd7-MT-2 (PDB: 1MRT, 2MRT, 4MT2) rat Cd5Zn2-MT-2 (Braun et al. 1992, PNAS USA 89:10124-10128, not in PDB) Known taxonomic range: vertebrata Multiple sequence alignment: yes Phylogenetic trees: yes Subdivisions: m1: mammalian MT-1 m2: mammalian MT-2 m3: mammalian MT-3 m4: mammalian MT-4 m : mammalian MT a1: avian MT-1 a2: avian MT-2 a : avian MT r : reptilian MT t : teleost MT s : sharks MT b : batracian MT Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ MT1_BOVIN (P58280) M1 AA MT1A_BOVIN (P67983) m1 c AA/NA MT1H_BOVIN (P55942) m AA MT2_BOVIN (P68301) m2 AA MT2H_BOVIN (P55943) m AA MT1_CANLF (O19000) m1 AA/NA MT2_CANLF (Q9XST5) m2 AA/NA MT1_CRIGR (P02804) m1 NA MT2_CRIGR (P67981) m2 NA MT2_CRILO (P68041) m2 NA MT2_MESAU (P17808) m2 NA MT1A_HORSE (P02800) m1 v AA MT1B_HORSE (P02801) m2 AA MT1_MOUSE (P02802) m1 c AA/NA MT2_MOUSE (P02798) m2 c AA/NA MT1A_PIG (P49068) m1 c NA MT1C_PIG (P79376) m1 NA MT1D_PIG (P79377) m1 NA MT1E_PIG (P79431) m1 NA MT1F_PIG (P79378) m1 NA MT2A_PIG (P79379) m2 NA MT2B_PIG (P79380) m2 NA MT1A_RABIT (P11957) m1 AA/NA MT2A_RABIT (P18055) m AA MT2B_RABIT (P80289) m AA MT2C_RABIT (P80290) m AA MT2D_RABIT (P80291) m AA MT2E_RABIT (P80292) m AA MT1_RAT (P02803) m1 AA/NA MT2_RAT (P04355) m2 AA/NA MT1A_SHEEP (P67982) m1 c NA MT1B_SHEEP (P09577) m1 NA MT1C_SHEEP (P09578) m1 NA MT2_SHEEP (P68302) m2 NA MT2_STECO (P14425) m1 AA MT1_CHLAE (P02797) m1 NA MT2_CHLAE (P68304) m2 NA MT1A_HUMAN (P04731) m1 NA MT1B_HUMAN (P07438) m1 NA MT1E_HUMAN (P04732) m1 AA/NA MT1F_HUMAN (P04733) m1 AA/NA MT1G_HUMAN (P13640) m1 AA/NA MT1H_HUMAN (P80294) m1 AA/NA MT1L_HUMAN (Q93083) m1 AA/NA MT1M_HUMAN (Q8N339) m1 NA MT1X_HUMAN (P80297) m1 AA/NA MT2_HUMAN (P02795) m2 AA/NA MT2_MACFA (P68303) m2 NA MT2_PONAB (Q5NVS0) m2 NA MT3_BOSMU (Q2MJS5) m3 NA MT3_BOVIN (P37359) m3 AA MT3_HORSE (P37360) m3 AA MT3_HUMAN (P25713) m3 AA/NA MT3_MACFA (Q2PFZ0) m3 NA MT3_MOUSE (P28184) m3 NA MT3_PIG (P55944) m3 NA MT3_RABIT (Q2PS21) m3 NA MT3_RAT (P37361) m3 NA MT3_SHEEP (Q8MKE4) m3 NA MT4_CANLF (Q9TUI5) m4 NA MT4_HUMAN (P47944) m4 NA MT4_MOUSE (P47945) m4 NA MT_BALMY (O18842) m NA MT_ANAPL (P68494) a1 AA/NA MT_CAIMO (P68495) a1 AA/NA MT_CHICK (P68497) a1 AA/NA MT1_COLLI (P15786) a1 AA MT2_COLLI (P15787) a2 AA MTA_COLVI (P27086) a p NA MTB_COLVI (P27087) a p NA MT_MELGA (P68498) a1 NA MT_PHACO (P68499) a1 p NA MT_PODSI (Q708T3) r NA MT1_DANRE (P52722) t NA MT2_DANRE (Q7ZSY6) t NA MT_CARAU (P52723) t c NA MTA_CARCW (Q8AWG2) t NA MTB_CARCW (Q8AWG1) t NA MTA_CHAAC (O93593) t NA MTB_CHAAC (P52724) t NA MTA_CHIHA (P68506) t NA MTB_CHIHA (P62711) t NA MTA_CHIRA (P62338) t NA MTB_CHIRA (P62679) t NA MT1_CYPCA (O13269) t NA MT2_CYPCA (Q9I9I0) t NA MTA_CYPS1 (Q92044) t NA MTB_DICLA (Q9PTG9) t NA MT_ESOLU (P25127) t NA MT_GADMO (P51902) t c NA MT_GOBCO (Q800D3) t NA MTA_GYMAC (P68507) t NA MTB_GYMAC (P62713) t NA MT_ICTPU (O93571) t NA MT_LITMO (Q8UVY1) t NA MT_LIZAU (O13257) t NA MTB_MORSA (P62712) t NA MT_BARBB (P25128) t NA MTA_NOTNE (P62339) t NA MTB_NOTNE (P62680) t NA MTA_ONCMY (P68503) t NA MTB_ONCMY (P68501) t NA MT_OREAU (Q7ZZP9) t NA MT_OREMO (P52726) t c NA MT_ORYLA (Q6S4N8) t NA MTA_PSEBE (O93609) t NA MTB_PSEBE (P62678) t NA MTA_PAGBO (P68508) t NA MTB_PAGBO (P62681) t NA MT_PAGMA (Q9IB50) t NA MTA_PARCR (O93450) t NA MTB_PARCR (P62682) t NA MT_PERFL (P52725) t NA MT_PLEAT (Q6XUW5) t NA MT_PLEPL (P07216) t AA/NA MT_PSEAM (P55945) t AA/NA MT_RUTRU (P80593) t AA MTA_SALAL (P68505) t c NA MTB_SALAL (P68502) t c NA MTA_SALSA (P68504) t NA MTB_SALSA (P52720) t NA MTA_SPAAU (P52727) t NA MTA_THECR (P52721) t NA MT_ZOAVI (P52728) t NA MT_SCYTO (Q6J1T3) s NA MT_AMBME (O42152) b NA MT_XENLA (Q05890) b NA ===================== Family 2: mollusc MTs ===================== Pattern: C-x-C-x(3)-C-T-G-x(3)-C-x-C-x(3)-C-x-C-K 3D structure status: not available Known taxonomic range: pelecypoda, gastropoda Multiple sequence alignment: yes Phylogenetic trees: yes Subdivisions: mo1: mussel MT-1 mo2: mussel MT-2 mog: gastropod MT mo : other mollusc MT Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ MT_CRAVI (P23038) mo AA/NA MT_DREPO (Q94550) mo NA MT10A_MYTED (P80246) mo1 AA/NA MT10B_MYTED (O62554) mo1 NA MT12_MYTED (P80247) mo1 c AA/NA MT13_MYTED (P80248) mo1 AA/NA MT14_MYTED (P80249) mo1 AA/NA MT21_MYTED (P80251) mo2 v AA MT22_MYTED (P80252) mo2 AA/NA MT23A_MYTED (P69153) mo2 AA MT23B_MYTED (P80258) mo2 AA MT23A_MYTGA (P69154) mo2 NA MT_PERVI (Q9U568) mo c NA MT_ARIAR (P55946) mog v AA MTCD_HELPO (P33187) mog AA MTCU_CALSI (Q9U620) mog NA MTCU_HELPO (P55947) mog AA ======================== Family 3: crustacean MTs ======================== Pattern: P-[GD]-P-C-C-x(3,4)-C-x-C 3D structure status: available for blue crab Cd6-MT-I (PDB: 1DMC, 1DMD, 1DME, 1DMF) for mud crab Cd6-MT1 (Not yet in PDB) Known taxonomic range: crustacea Multiple sequence alignment: yes Phylogenetic trees: yes Subdivisions: c : crustacean MT c1: crustacean MT-1 c2: crustacean MT-2 Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ MT_CARMA (P55948) c2 v AA MT1_CALSI (P55949) c1 v AA MT2_CALSI (P55950) c2 v AA MT1_SCYSE (P02805) c1 AA MT2_SCYSE (P02806) c2 AA MT1_HOMAM (P29499) c AA MT_ASTAS (P55951) c v AA MT_POTPO (P55952) c AA =========================== Family 4: echinodermata MTs =========================== Pattern: P-D-x-K-C-V-C-C-x(5)-C-x-C-x(4)-C-C-x(4)-C-C-x(4,6)-C-C 3D structure status: available for sea urchin Cd7-MTA (1qjk, 1qjl) Known taxonomic range: echinoidea Multiple sequence alignment: yes Phylogenetic trees: yes Subdivisions: e1: echinodermata MT type 1 e2: echinodermata MT type 2 Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ MT_LYTPI (O02033) e2 NA MT_PARLI (P80367) e2 AA MTA_STRPU (P04734) e1 c NA MTB_STRPU (Q27287) e1 NA MTA_SPHGR (Q26497) e2 p NA MTB_SPHGR (Q26496) e2 p NA MT_STENE (P55953) e1 NA ===================== Family 5: diptera MTs ===================== Pattern: C-G-x(2)-C-x-C-x(2)-Q-x(5)-C-x-C-x(2)-D-C-x-C 3D structure status: not available Known taxonomic range: diptera Multiple sequence alignment: yes Phylogenetic trees: no Subdivisions: d1: diptera MT type 1 d2: diptera MT type 2 Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ MT1_DROAN (P61873) d1 NA MT1_DROME (P04357) d1 NA MT1_DROSI (P61874) d1 NA MT2_DROME (P11956) d2 NA MT3_DROME (Q9VDN2) d2 NA MT4_DROME (Q8I9B4) d2 NA ====================== Family 6: nematoda MTs ====================== Pattern: K-C-C-x(3)-C-C 3D structure status: not available Known taxonomic range: secernentea Multiple sequence alignment: yes Phylogenetic trees: no Subdivisions: n1: nematoda MT type 1 n2: nematoda MT type 2 Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ MT1_CAEEL (P17511) n1 c NA MT2_CAEEL (P17512) n2 NA ===================== Family 7: ciliata MTs ===================== Pattern: - 3D structure status: not available Known taxonomic range: ciliata (protozoa) Multiple sequence alignment: no Phylogenetic trees: no Subdivisions: ci: ciliata MT Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ MT1_TETPI (P80394) ci AA/NA MT1_TETPY (O97388) ci AA/NA MT1_TETTH (Q8T6B3) ci NA MTCD_TETTH (Q8WSW3) ci NA ===================== Family 8: fungi-I MTs ===================== Pattern: C-G-C-S-x(4)-C-x-C-x(3,4)-C-x-C-S-x-C 3D structure status: available for N.crassa Cu6-MT (PDB: 1T2Y) Known taxonomic range: basidiomycotina, deuteromycotina, ascomycotina Multiple sequence alignment: yes Phylogenetic trees: no Subdivisions: f1: fungi-I MT Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ MT_AGABI (P04358) f1 AA MT1_COLGL (Q99334) f1 NA MT2_COLGL (Q00369) f1 NA MT1_NECLU (P84865) f1 AA MT_NEUCR (P02807) f1 c AA/NA ====================== Family 9: fungi-II MTs ====================== Pattern: - 3D structure status: not available Known taxonomic range: deuteromycotina Multiple sequence alignment: no Phylogenetic trees: no Subdivisions: f2: fungi-II MT Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ MT1_CANGA (P15113) f2 AA/NA ======================== Family 10: fungi-III MTs ======================== Pattern: - 3D structure status: not available Known taxonomic range: deuteromycotina Multiple sequence alignment: no Phylogenetic trees: no Subdivisions: f3 Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ MT2_CANGA (P15114) f3 v AA/NA ======================= Family 11: fungi-IV MTs ======================= Pattern: C-X-K-C-x-C-x(2)-C-K-C 3D structure status: not available Known taxonomic range: ascomycotina Multiple sequence alignment: no Phylogenetic trees: no Subdivisions: f4: fungi-IV MT Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ MT1_YARLI (P41927) f4 NA MT2_YARLI (P41928) f4 NA MT3_YARLI (Q9HFD0) f4 NA MT4_YARLI (Q9HFC9) f4 NA ====================== Family 12: fungi-V MTs ====================== Pattern: - 3D structure status: PDB: 1AOO, 1AQQ, 1AQR, 1AQS Known taxonomic range: ascomycotina Multiple sequence alignment: yes Phylogenetic trees: no Subdivisions: f5: fungi-V MT Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ MTCU1_YEAST (P0CX80) f5 AA/NA MTCU2_YEAST (P0CX81) f5 AA/NA ======================= Family 13: fungi-VI MTs ======================= Pattern: - 3D structure status: not available Known taxonomic range: ascomycotina Multiple sequence alignment: no Phylogenetic trees: no Subdivisions: f6: fungi-VI MT Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ CRS5_YEAST (P41902) f6 NA ========================= Family 14: prokaryota MTs ========================= Pattern: K-C-A-C-x(2)-C-L-C 3D structure status: not available Known taxonomic range: cyanobacteria Multiple sequence alignment: yes Phylogenetic trees: no Subdivisions: pr: prokaryota MT Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ MT_SYNE7 (P30331) pr AA/NA MT_SYNSP (P08002) pr AA MT_THEVL (P30565) pr NA ==================== Family 15: plant MTs ==================== Pattern: [YFH]-x(5,25)-C-[SKD]-C-[GA]-[SDPAT]-x(0,1)-C-x-[CYF] Note: yields all plant sequences, but also MTCU_HELPO (P55947) and the non-MT ITB3_HUMAN (P05106) 3D structure status: not available Known taxonomic range: angiospermae (magnolophyta) Multiple sequence alignment: yes Phylogenetic trees: yes Subdivisions: p1 : plant MT type 1 p2 : plant MT type 2 p3 : plant MT type 3 p21: plant MT type 2x1 pec: plant EC MT-like protein Swiss-Prot Subdiv. Rem. Source Entry name AC -------------------- ------- ---- ------ MT1_CASGL (Q39511) p1 NA MT1_CICAR (Q39458) p1 NA MT1_FESRU (O24528) p1 NA MT1_HORVU (P26571) p1 NA MT1_MAIZE (P30571) p1 NA MT1A_ORYSI (A2ZH20) p1 NA MT1A_ORYSJ (P0C5B3) p1 NA MT1B_ORYSJ (Q10N03) p1 NA MT1_PEA (P20830) p1 NA MT1_TRIRP (P43399) p1 NA MT1A_VICFA (Q41669) p1 NA MT1B_VICFA (Q41670) p1 NA MT1_WHEAT (P43400) p1 NA MT2_ACTDE (P43390) p2 NA MT2A_ARATH (P25860) p2 c NA MT2B_ARATH (Q38805) p2 NA MT21_BRAJU (P56168) p2 NA MT22_BRAJU (P69163) p2 NA MT23_BRAJU (P56170) p2 NA MT25_BRAJU (P56172) p2 NA MT2_BRANA (Q96353) p2 p NA MT2_BRACM (P69164) p2 c NA MT2_BRARP (Q39269) p2 NA MT2_CICAR (Q39459) p2 p NA MT1_COFAR (P43396) p2 NA MT2_FRAAN (P93134) p2 NA MT2_MALDO (O24058) p2 NA MT2_MUSAC (O22319) p2 NA MT2_NICGU (Q40396) p2 NA MT2_NICPL (Q40410) p2 NA MT2A_ORYSJ (P94029) p2 NA MT2B_ORYSJ (Q5JM82) p2 NA MT2C_ORYSI (A2XZL0) p2 NA MT2C_ORYSJ (A3AZ88) p2 NA MT2_RICCO (P30564) p2 NA MT2A_SOLLC (Q40157) p2 NA MT2B_SOLLC (Q40158) p2 c NA MT2X_SOLLC (Q43512) p2 NA MT2Y_SOLLC (Q43513) p2 NA MT2Z_SOLLC (Q43515) p2 NA MT2_TRIRP (P43398) p2 NA MT2_VICFA (Q41657) p2 NA MT1_ERYGU (P20238) p2 c NA MT1A_ARATH (P43392) p21 NA MT1B_ARATH (Q38803) p21 NA MT1C_ARATH (Q38804) p21 NA MT54_BRANA (P43402) p21 NA MT3_ACTDE (P43389) p3 NA MT3_CARPA (Q96386) p3 NA MT3_MALDO (O24059) p3 NA MT3_MUSAC (Q40256) p3 NA MT3A_ORYSI (A2WLS0) p3 NA MT3A_ORYSJ (A1YTM8) p3 NA MT3B_ORYSI (A2Y1D7) p3 NA MT3B_ORYSJ (A3B0Y1) p3 NA MT3_PICGL (Q40854) p3 NA MT3_PRUAV (O48951) p3 NA MT4A_ORYSJ (Q0IMG5) p4 NA MT4B_ORYSJ (Q2QNE8) p4 NA MT4C_ORYSJ (Q2QNC3) p4 NA MT4A_ARATH (P93746) pec NA MT4B_ARATH (Q42377) pec NA EC_MAIZE (P43401) pec NA MT21A_ORYSJ (Q109B0) pec NA EC1_WHEAT (P30569) pec c AA/NA EC3_WHEAT (P30570) pec NA ========================================================================== Family 99: phytochelatins and other non-proteinaceous MT-like polypeptides ========================================================================== Note: gammaglutamyl-cysteinyl units, these are not proteins. 3D structure status: not available Known taxonomic range: viridiplantae Subdivisions: not defined ------------------------------------------------------------------------------ ================================================================== Definition of the metallothionein superfamily and its subdivisions ================================================================== The metallothionein superfamily is defined phenomenologically as comprising all polypeptides which resemble equine renal metallothionein in several of their features (Nordberg & Kojima 1979, Fowler et al. 1987). Such general features are low molecular weight, high metal content, characteristic amino acid composition (high Cys content, low content of aromatic amino acid residues), unique amino acid sequence with characteristic distribution of Cys, i.e. Cys-X-Cys and spectroscopic manifestations characteristic of metal thiolate clusters. A MT family subsumes MTs which share a particular set of sequence specific characters. Members of a family can belong to only one family and are thought to be evolutionary related. The inclusion of an MT in a family presupposes that its amino acid sequence is alignable with that of all members. A common and exclusive sequence pattern, a profile and a phylogenetic tree can therefore be connected with each family. Each family is identified by its number and its taxonomic range. An example is Family 1: vertebrate MTs. A MT subfamily contains MTs which in addition to the family characters share a set of more stringent phylogenetic features. These extra criteria are usually specific monophyletic relationships among the sequences of proteins and/or of nucleotide segments in the genes (5' or 3' untranscribed portion of the genes, 5' or 3' untranslated portions of the nucleotide sequences, exons, introns). If relevant other differentiating criteria can also be included, such as presence, conservation or repetition of sequence patterns. A subfamily is usually abbreviated with a letter character followed, if necessary, with an arabic number. An example is m1: mammalian MT-1. A MT subgroup represents, as a result of statistically validated phylogenetic analyses, a branch of MT sequences of a subfamily which is clearly distinguishable in a tree by its monophyletic character. An example is m2U2: ungulate MT-2, subgroup of the m2 subfamily. Isoforms or allelic forms are specifiable as members of subgroups, subfamilies and families. They are named using the nomenclature system defined in Kojima et al. (submitted), i.e. human MT-1E. In addition, in cases where it is justifiable, one can define clans. A clan is a set of partial or total amino acid or polynucleotide sequences, subgroups, subfamilies, families or combinations of them which share characters not defined by the above classification criteria. They can be related to common spatial structure, thermodynamic properties, metal binding properties, functionally related characters or other relevant features. A clan is defined by the property common to its members. The abbreviation should reflect this property. ----------------------------------------------------------------------- Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms Distributed under the Creative Commons Attribution (CC BY 4.0) License -----------------------------------------------------------------------