Letunic et al. (2017) Nucleic Acids Res doi: 10.1093/nar/gkx922
Letunic et al. (2020) Nucleic Acids Res doi: 10.1093/nar/gkaa937

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CY Cystatin-like domain

SMART accession number:	SM00043
Description:	Cystatins are a family of cysteine protease inhibitors that occur mainly as single domain proteins. However some extracellular proteins such as kininogen, His-rich glycoprotein and fetuin also contain these domains.
Interpro abstract (IPR000010):	Cystatins are a family of cysteine protease inhibitors belonging to MEROPS inhibitor family I25, clan IH [ (PUBMED:2107324) (PUBMED:14587292) (PUBMED:1855589) ]. They mainly inhibit peptidases belonging to peptidase families C1 (papain family) and C13 (legumain family). They occur mainly as single domain proteins. However, some extracellular proteins such as kininogen, His-rich glycoprotein and fetuin also contain these domains.
GO function:	cysteine-type endopeptidase inhibitor activity (GO:0004869)
Family alignment:	View or CHROMA formatHMM/Web logoCLUSTALW formatMSF formatFASTA formatPIR format

There are 9885 CY domains in 7379 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Taxonomic distribution of proteins containing CY domain.

  This tree includes only several representative species. The complete taxonomic breakdown of all proteins with CY domain is also avaliable.

  Click on the protein counts, or double click on taxonomic names to display all proteins containing CY domain in the selected taxonomic class.

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Brown WM, Dziegielewska KM
  • Friends and relations of the cystatin superfamily--new members and their evolution.
  • Protein Sci. 1997; 6: 5-12
  • Display abstract

  • The cystatin "superfamily" encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. In recent years, several new members of the superfamily have characterized, including proteins from insects and plants. Based on partial amino acid homology, new members, such as the invariant chain (Ii), and the transforming growth factor-beta receptor type II (TGF-beta receptor II) may, in fact, represent members of an emerging family within the superfamily that may have used some common building blocks to form functionally diverse proteins. Cystatin super-family members have been found throughout evolution and members of each family of the superfamily are present in mammals today. In this review, the new and older, established members of the family are arranged into a possible evolutionary order, based on sequence homology and functional similarities.

  • Turk V, Bode W
  • The cystatins: protein inhibitors of cysteine proteinases.
  • FEBS Lett. 1991; 285: 213-9
  • Display abstract

  • The last decade has witnessed enormous progress of protein inhibitors of cysteine proteinases concerning their structures, functions and evolutionary relationships. Although they differ in their molecular properties and biological distribution, they are structurally related proteins. All three inhibitory families, the stefins, the cystatins and the kininogens, are members of the same superfamily. Recently determined crystal structures of chicken cystatin and human stefin B established a new mechanism of interaction between cysteine proteinases and their inhibitors which is fundamentally different from the standard mechanism for serine proteinases and their inhibitors.

• Disease (disease genes where sequence variants are found in this domain)

• SwissProt sequences and OMIM curated human diseases associated with missense mutations within the CY domain.

  Protein	Disease
  Cystatin-C (P01034) (SMART)	OMIM:105150: Cerebral amyloid angiopathy OMIM:604312: Cerebral amyloid angiopathy OMIM:105150:
  Alpha-2-HS-glycoprotein (P02765) (SMART)	OMIM:138680: ALPHA-2-HS-GLYCOPROTEIN; AHSG
  Cystatin-B (P04080) (SMART)	OMIM:601145: Epilepsy, progressive myoclonic 1 OMIM:254800:

• Metabolism (metabolic pathways involving proteins which contain this domain)

• % proteins involved KEGG pathway ID Description 100.00 map04610 Complement and coagulation cascades This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with CY domain which could be assigned to a KEGG orthologous group, and not all proteins containing CY domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of CY domains in PDB

  PDB code	Main view	Title
  1a67		CHICKEN EGG WHITE CYSTATIN WILDTYPE, NMR, 16 STRUCTURES
  1a90		RECOMBINANT MUTANT CHICKEN EGG WHITE CYSTATIN, NMR, 31 STRUCTURES
  1cew		THE 2.0 ANGSTROMS X-RAY CRYSTAL STRUCTURE OF CHICKEN EGG WHITE CYSTATIN AND ITS POSSIBLE MODE OF INTERACTION WITH CYSTEINE PROTEINASES
  1cyu		SOLUTION NMR STRUCTURE OF RECOMBINANT HUMAN CYSTATIN A UNDER THE CONDITION OF PH 3.8 AND 310K
  1cyv		SOLUTION NMR STRUCTURE OF RECOMBINANT HUMAN CYSTATIN A UNDER THE CONDITION OF PH 3.8 AND 310K
  1dvc		SOLUTION NMR STRUCTURE OF HUMAN STEFIN A AT PH 5.5 AND 308K, NMR, MINIMIZED AVERAGE STRUCTURE
  1dvd		SOLUTION NMR STRUCTURE OF HUMAN STEFIN A AT PH 5.5 AND 308K, NMR, 17 STRUCTURES
  1eqk		SOLUTION STRUCTURE OF ORYZACYSTATIN-I, A CYSTEINE PROTEINASE INHIBITOR OF THE RICE, ORYZA SATIVA L. JAPONICA
  1g96		HUMAN CYSTATIN C; DIMERIC FORM WITH 3D DOMAIN SWAPPING
  1gd3		refined solution structure of human cystatin A
  1gd4		SOLUTION STRUCTURE OF P25S CYSTATIN A
  1n9j		Solution Structure of the 3D domain swapped dimer of Stefin A
  1nb3		Crystal structure of stefin A in complex with cathepsin H: N-terminal residues of inhibitors can adapt to the active sites of endo-and exopeptidases
  1nb5		Crystal structure of stefin A in complex with cathepsin H
  1r4c		N-Truncated Human Cystatin C; Dimeric Form With 3D Domain Swapping
  1rn7		Structure of human cystatin D
  1roa		Structure of human cystatin D
  1stf		THE REFINED 2.4 ANGSTROMS X-RAY CRYSTAL STRUCTURE OF RECOMBINANT HUMAN STEFIN B IN COMPLEX WITH THE CYSTEINE PROTEINASE PAPAIN: A NOVEL TYPE OF PROTEINASE INHIBITOR INTERACTION
  1tij		3D Domain-swapped human cystatin C with amyloid-like intermolecular beta-sheets
  1yvb		the Plasmodium falciparum Cysteine Protease Falcipain-2
  2ch9		Crystal structure of dimeric human cystatin F
  2l4v		Three Dimensional Structure of Pineapple Cystatin
  2mzv		2MZV
  2oct		Stefin B (Cystatin B) tetramer
  2w9p		Crystal Structure of Potato Multicystatin
  2w9q		Crystal Structure of Potato Multicystatin-P212121
  3gax		Crystal structure of monomeric human cystatin C stabilized against aggregation
  3ima		Complex strcuture of tarocystatin and papain
  3k9m		Cathepsin B in complex with stefin A
  3kfq		Unreduced cathepsin V in complex with stefin A
  3kse		Unreduced cathepsin L in complex with stefin A
  3l0r		Crystal Structure of Salivary Cystatin from the Soft Tick Ornithodoros moubata
  3lh4		Crystal Structure of Sialostatin L2
  3mwz		Crystal structure of the selenomethionine derivative of the L 22,47,100 M mutant of sialostatin L2
  3nx0		Hinge-loop mutation can be used to control 3D domain swapping and amyloidogenesis of human cystatin C
  3ps8		Crystal structure of L68V mutant of human cystatin C
  3qrd		Crystal structure of L68V mutant of human cystatin C
  3s67		Crystal structure of V57P mutant of human cystatin C
  3sva		Crystal structure of V57D mutant of human cystatin C
  3ul5		Saccharum officinarum canecystatin-1 in space group C2221
  3ul6		Saccharum officinarum canecystatin-1 in space group P6422
  4ccv		Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: Implications for the regulation of angiogenesis
  4it7		Crystal structure of Al-CPI
  4lzi		Characterization of Solanum tuberosum Multicystatin and Significance of Core Domains
  4n6l		4N6L
  4n6m		4N6M
  4n6n		4N6N
  4n6o		4N6O
  4n6t		Adhiron: a stable and versatile peptide display scaffold - full length adhiron
  4n6u		Adhiron: a stable and versatile peptide display scaffold - truncated adhiron
  4n6v		Partial rotational order disorder structure of human stefin B
  4tx4		4TX4
  4zm8		4ZM8
  5a0o		5A0O
  5elj		5ELJ
  5elu		5ELU
  5eql		5EQL

• Links (links to other resources describing this domain)

• PROSITE	CY_DOMAIN
  INTERPRO	IPR000010
  PFAM	cystatin

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