Seroatlas · Human Serome Atlas

A2ML1

Alpha-2-macroglobulin-like protein 1

Also known as: A2ML1_HUMAN, CPAMD9, FLJ25179, p170

Cross-references: UniProt · Ensembl · Human Protein Atlas · GeneCards · NCBI Gene

Protein identityUniProt · HPA

UniProt accession: A8K2U0
Gene: A2ML1
Ensembl: ENSG00000166535
Chromosome: 12
Canonical length: 1454 aa
Protein class: Disease related genes, Predicted intracellular proteins, Predicted secreted proteins
Secretome location: Secreted in other tissues

OverviewNCBI Gene

This gene encodes a member of the alpha-macroglobulin superfamily. The encoded protein is thought to be an N-glycosylated monomeric protein that acts as an inhibitor of several proteases. It has been shown to form covalent interactions with proteases, and has been reported as the p170 antigen recognized by autoantibodies in the autoimmune disease paraneoplastic pemphigus (PNP; PMID:20805888). Mutations in these gene have also been associated with some cases of Noonan syndrome (NS; PMID:24939586) as well as some cases of otitis media (PMID:26121085). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

Canonical amino-acid sequenceUniProt

1454 residues, UniProt reviewed canonical sequence.

>A8K2U0|A2ML1
     1  MWAQLLLGML ALSPAIAEEL PNYLVTLPAR LNFPSVQKVC LDLSPGYSDV KFTVTLETKD
    61  KTQKLLEYSG LKKRHLHCIS FLVPPPAGGT EEVATIRVSG VGNNISFEEK KKVLIQRQGN
   121  GTFVQTDKPL YTPGQQVYFR IVTMDSNFVP VNDKYSMVEL QDPNSNRIAQ WLEVVPEQGI
   181  VDLSFQLAPE AMLGTYTVAV AEGKTFGTFS VEEYVLPKFK VEVVEPKELS TVQESFLVKI
   241  CCRYTYGKPM LGAVQVSVCQ KANTYWYREV EREQLPDKCR NLSGQTDKTG CFSAPVDMAT
   301  FDLIGYAYSH QINIVATVVE EGTGVEANAT QNIYISPQMG SMTFEDTSNF YHPNFPFSGK
   361  IRVRGHDDSF LKNHLVFLVI YGTNGTFNQT LVTDNNGLAP FTLETSGWNG TDVSLEGKFQ
   421  MEDLVYNPEQ VPRYYQNAYL HLRPFYSTTR SFLGIHRLNG PLKCGQPQEV LVDYYIDPAD
   481  ASPDQEISFS YYLIGKGSLV MEGQKHLNSK KKGLKASFSL SLTFTSRLAP DPSLVIYAIF
   541  PSGGVVADKI QFSVEMCFDN QVSLGFSPSQ QLPGAEVELQ LQAAPGSLCA LRAVDESVLL
   601  LRPDRELSNR SVYGMFPFWY GHYPYQVAEY DQCPVSGPWD FPQPLIDPMP QGHSSQRSII
   661  WRPSFSEGTD LFSFFRDVGL KILSNAKIKK PVDCSHRSPE YSTAMGAGGG HPEAFESSTP
   721  LHQAEDSQVR QYFPETWLWD LFPIGNSGKE AVHVTVPDAI TEWKAMSFCT SQSRGFGLSP
   781  TVGLTAFKPF FVDLTLPYSV VRGESFRLTA TIFNYLKDCI RVQTDLAKSH EYQLESWADS
   841  QTSSCLCADD AKTHHWNITA VKLGHINFTI STKILDSNEP CGGQKGFVPQ KGRSDTLIKP
   901  VLVKPEGVLV EKTHSSLLCP KGKVASESVS LELPVDIVPD STKAYVTVLG DIMGTALQNL
   961  DGLVQMPSGC GEQNMVLFAP IIYVLQYLEK AGLLTEEIRS RAVGFLEIGY QKELMYKHSN
  1021  GSYSAFGERD GNGNTWLTAF VTKCFGQAQK FIFIDPKNIQ DALKWMAGNQ LPSGCYANVG
  1081  NLLHTAMKGG VDDEVSLTAY VTAALLEMGK DVDDPMVSQG LRCLKNSATS TTNLYTQALL
  1141  AYIFSLAGEM DIRNILLKQL DQQAIISGES IYWSQKPTPS SNASPWSEPA AVDVELTAYA
  1201  LLAQLTKPSL TQKEIAKATS IVAWLAKQHN AYGGFSSTQD TVVALQALAK YATTAYMPSE
  1261  EINLVVKSTE NFQRTFNIQS VNRLVFQQDT LPNVPGMYTL EASGQGCVYV QTVLRYNILP
  1321  PTNMKTFSLS VEIGKARCEQ PTSPRSLTLT IHTSYVGSRS SSNMAIVEVK MLSGFSPMEG
  1381  TNQLLLQQPL VKKVEFGTDT LNIYLDELIK NTQTYTFTIS QSVLVTNLKP ATIKVYDYYL
  1441  PDEQATIQYS DPCE

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against A2ML1 can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability: Secreted
Secreted: Yes
Transmembrane segments: 0
Mean surface accessibility (rSASA): 0.26
Highest tissue expression: 538 nTPM

Expression across tissuesHPA

Tissue

esophagus: 538 nTPM
vagina: 200 nTPM
cervix: 189 nTPM
salivary gland: 86 nTPM
skin: 69 nTPM
tonsil: 48 nTPM

Single-cell type

esophageal apical cells: 4,253 nCPM
esophageal suprabasal cells: 1,300 nCPM
suprabasal keratinocytes: 615 nCPM
esophageal basal cells: 135 nCPM
sertoli cells: 87 nCPM
endometrial luminal cells: 81 nCPM

Immune cell

basophil: 0.3 nTPM
non-classical monocyte: 0.3 nTPM
neutrophil: 0.2 nTPM
classical monocyte: 0.1 nTPM
gdT-cell: 0.1 nTPM
intermediate monocyte: 0.1 nTPM

Brain region

thalamus: 14 nTPM
midbrain: 12 nTPM
hypothalamus: 10 nTPM
cerebral cortex: 9.2 nTPM
amygdala: 9 nTPM
basal ganglia: 8.9 nTPM

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about A2ML1.

Disease | AllUniProt

Conditions A2ML1 is implicated in, by any mechanism.

Otitis media (OM) MIM:166760

Disease | GeneticClinVar

1 pathogenic / likely-pathogenic of 1,991 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

Otitis media, susceptibility to
Otitis media

ReferencesPubMed · IEDB

Publications for A2ML1 from three distinct lines of evidence, kept separate because they answer different questions: whether antibodies are directed at the protein, whether a B-cell epitope has been mapped on it, and whether a T-cell epitope has. Each is labelled with its source.

Reference: AutoantibodyPubMed

2 publications

Anti-α-2-macroglobulin-like-1 autoantibodies are detected frequently and may be pathogenic in paraneoplastic pemphigus.
2013 · J Invest Dermatol · RCR 1.7 · 43 citations
Detection of autoantibodies against alpha-2-macroglobulin-like 1 in paraneoplastic pemphigus sera utilizing novel green fluorescent protein-based immunoassays.
2020 · J Dermatol Sci · RCR 0.5 · 6 citations

Reference: T cellIEDB

1 publication

High-throughput determination of the antigen specificities of T cell receptors in single cells.
2018 · Nat Biotechnol · RCR 4.5 · 163 citations

Sources: PubMed — antigen-level antibody evidence from a custom retrieval. Records matching a controlled set of autoantibody terms (the MeSH descriptors Autoantibodies and Autoantigens, with title and abstract term variants) were obtained through NCBI E-utilities, and their titles and abstracts parsed for constructions that direct an antibody at a named protein rather than for co-occurrence. Captured names were resolved against UniProt nomenclature and each antigen adjudicated individually against the source text. IEDB — curated epitope assays from the Immune Epitope Database (Vita et al., Nucleic Acids Research 2019). Bibliographic records from PubMed and MeSH, U.S. National Library of Medicine; citation metrics from NIH iCite (Hutchins et al., PLoS Biology 2016). Titles link to PubMed; abstracts are not reproduced here. The NLM does not endorse this analysis.

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance): 0.95
gnomAD pLI: 0
gnomAD missense Z: 0.33
DepMap mean gene effect: 0.07
DepMap dependency class: none

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 4% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

regulation of endopeptidase activity

Molecular functions

Cellular components

Protein domainsUniProt · Pfam · InterPro

KeywordsUniProt

Antibody and autoantibody relevanceSeroatlas analysis

Seroatlas reads A2ML1 as an antibody target. Whether an autoantibody or antibody against A2ML1 could matter depends on whether native A2ML1 is physically reachable, whether the body needs it intact, and whether it acts in a disease-relevant tissue.

A2ML1 is annotated as secreted, so native A2ML1 circulates and is directly accessible to antibodies. Secreted and cell-surface proteins are the autoantibody targets most likely to act like drugs, blocking or depleting the native protein.

Source-annotated serology context

The source annotations explicitly mention antibody, autoantibody, autoantigen, or autoimmune context. This is biological context, not study-specific reactivity.

It has been shown to form covalent interactions with proteases, and has been reported as the p170 antigen recognized by autoantibodies in the autoimmune disease paraneoplastic pemphigus (PNP; PMID:20805888).

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