Protease propeptides/inhibitors superfamily

SCOP classification

• Root: SCOP hierarchy in SUPERFAMILY [ 0] (11)
• Class: Alpha and beta proteins (a+b) [ 53931] (376)
• Fold: Ferredoxin-like [ 54861] (59)
• Superfamily: Protease propeptides/inhibitors [ 54897] (3)
• Families:
  • Pancreatic carboxypeptidase, activation domain [ 54898] (2)
  • Subtilase propeptides/inhibitors [ 54905] (3)
  • Prohormone convertase 1 pro-domain [ 75431]

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Superfamily statistics

	Genomes (835)	Uniprot 2018_03 genome	PDB chains (SCOP 1.75)
Domains	5,713	22,481	16
Proteins	5,672	22,308	16

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Functional annotation

• General category: Processes_IC
• Detailed category: Proteases

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Enzyme Commission (EC)

Highlighted in gray are those with FDR_all>0.001

	EC term	FDR (all)	IC level	SDEO level	Annotation (direct or inherited)
Enzyme Commission (EC)	Hydrolases	0	0.04271	--	DIRECT
Enzyme Commission (EC)	Tripeptidyl-peptidase I	0	2.259	--	DIRECT
Enzyme Commission (EC)	Oryzin	0.000000000003662	2.259	--	DIRECT
Enzyme Commission (EC)	Subtilisin	0.000000005031	2.259	--	DIRECT
Enzyme Commission (EC)	Carboxypeptidase A	0.00002229	2.56	--	DIRECT
Enzyme Commission (EC)	Acting on peptide bonds (peptide hydrolases)	0	0.5513	Least Informative	DIRECT
Enzyme Commission (EC)	Serine endopeptidases	0.0001429	0.9917	Moderately Informative	DIRECT
Enzyme Commission (EC)	Dipeptidyl-peptidases and tripeptidyl-peptidases	0.00002239	1.657	Informative	DIRECT
Enzyme Commission (EC)	Metallocarboxypeptidases	0	1.782	Highly Informative	DIRECT
Enzyme Commission (EC)	Furin	0.0000000000001568	1.958	Highly Informative	DIRECT
Enzyme Commission (EC)	Proprotein convertase 2	0.00000000008229	2.083	Highly Informative	DIRECT
Enzyme Commission (EC)	Proprotein convertase 1	0.000000001803	2.083	Highly Informative	DIRECT

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Worm Phenotype (WP)

Highlighted in gray are those with FDR_all>0.001

	WP term	FDR (all)	IC level	SDWP level	Annotation (direct or inherited)
Worm Phenotype (WP)	growth variant	0	0.4022	--	DIRECT
Worm Phenotype (WP)	postembryonic development variant	0	0.3347	--	DIRECT
Worm Phenotype (WP)	embryonic lethal	0	0.07108	--	DIRECT
Worm Phenotype (WP)	larval arrest	0	0.5677	--	DIRECT
Worm Phenotype (WP)	lethal	0	0.01121	--	DIRECT
Worm Phenotype (WP)	fertility variant	0	0.08329	--	DIRECT
Worm Phenotype (WP)	development variant	0	0.001706	--	DIRECT
Worm Phenotype (WP)	morphology variant	0	0.06117	--	DIRECT
Worm Phenotype (WP)	organism development variant	0	0.004279	--	DIRECT
Worm Phenotype (WP)	organism morphology variant	0	0.2011	--	DIRECT
Worm Phenotype (WP)	organ system physiology variant	0	0.05921	--	DIRECT
Worm Phenotype (WP)	organism physiology variant	0	0.1405	--	DIRECT
Worm Phenotype (WP)	organism homeostasis metabolism variant	0	0.1501	--	DIRECT
Worm Phenotype (WP)	reproductive system physiology variant	0	0.07209	--	DIRECT
Worm Phenotype (WP)	maternal sterile	0	0.171	--	DIRECT
Worm Phenotype (WP)	hermaphrodite sterile	0	0.1685	--	DIRECT
Worm Phenotype (WP)	embryonic development variant	0	0.06709	--	DIRECT
Worm Phenotype (WP)	hermaphrodite fertility variant	0	0.1278	--	DIRECT
Worm Phenotype (WP)	developmental growth variant	0	0.5677	--	DIRECT
Worm Phenotype (WP)	hermaphrodite fertility reduced	0	0.1672	--	DIRECT
Worm Phenotype (WP)	fertility reduced	0	0.09267	--	DIRECT
Worm Phenotype (WP)	body length variant	0.01439	1.346	--	INHERITED FROM: dumpy
Worm Phenotype (WP)	body width variant	0.01978	1.245	--	INHERITED FROM: dumpy
Worm Phenotype (WP)	body size variant	0.02825	1.202	--	INHERITED FROM: dumpy
Worm Phenotype (WP)	body morphology variant	0.03663	1.164	--	INHERITED FROM: dumpy
Worm Phenotype (WP)	physiology variant	1	0	--	INHERITED FROM: pericellular component development variant || hermaphrodite fertility variant || developmental growth variant || larval lethal || reproductive system physiology variant || organism homeostasis metabolism variant || lethal || larval development variant || basement membrane remodeling variant || organism physiology variant || development variant || hermaphrodite sterile || growth variant || hermaphrodite fertility reduced || embryonic development variant || embryonic lethal || larval growth variant || fertility variant || postembryonic development variant || larval arrest || organ system physiology variant || maternal sterile || organism development variant || fertility reduced
Worm Phenotype (WP)	sterile	1	0.161	--	INHERITED FROM: hermaphrodite sterile || maternal sterile
Worm Phenotype (WP)	larval lethal	0	0.6947	Least Informative	DIRECT
Worm Phenotype (WP)	larval development variant	0	0.5007	Least Informative	DIRECT
Worm Phenotype (WP)	larval growth variant	0	0.5677	Least Informative	DIRECT
Worm Phenotype (WP)	pericellular component development variant	0.000000000009504	1.216	Moderately Informative	DIRECT
Worm Phenotype (WP)	organism segment morphology variant	0.05959	1.064	Moderately Informative	INHERITED FROM: dumpy
Worm Phenotype (WP)	body region morphology variant	0.06024	1.045	Moderately Informative	INHERITED FROM: dumpy
Worm Phenotype (WP)	basement membrane remodeling variant	0.000000000001058	1.31	Informative	DIRECT
Worm Phenotype (WP)	dumpy	0.00091	1.753	Highly Informative	DIRECT

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Yeast Phenotype (YP)

Highlighted in gray are those with FDR_all>0.001

	YP term	FDR (all)	IC level	SDYP level	Annotation (direct or inherited)
Yeast Phenotype (YP)	competitive fitness	0	0.1389	--	DIRECT
Yeast Phenotype (YP)	fitness	0	0.1328	--	DIRECT

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Fly Anatomy (FA)

Highlighted in gray are those with FDR_all>0.001

	FA term	FDR (all)	IC level	SDFA level	Annotation (direct or inherited)
Fly Anatomy (FA)	multicellular structure	0	0.009143	--	DIRECT
Fly Anatomy (FA)	anatomical structure	1	0	--	INHERITED FROM: multicellular structure
Fly Anatomy (FA)	material anatomical entity	1	0	--	INHERITED FROM: multicellular structure

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Zebrafish Anatomy (ZA)

Highlighted in gray are those with FDR_all>0.001

	ZA term	FDR (all)	IC level	SDZA level	Annotation (direct or inherited)
Zebrafish Anatomy (ZA)	whole organism	0	0.004764	--	DIRECT
Zebrafish Anatomy (ZA)	midbrain	0.007154	1.74	--	INHERITED FROM: optic tectum
Zebrafish Anatomy (ZA)	brain	0.1127	1.161	--	INHERITED FROM: optic tectum
Zebrafish Anatomy (ZA)	anatomical system	0.6371	0.2245	--	INHERITED FROM: optic tectum
Zebrafish Anatomy (ZA)	anatomical group	0.6667	0.1889	--	INHERITED FROM: optic tectum
Zebrafish Anatomy (ZA)	cavitated compound organ	0.7934	0.5472	--	INHERITED FROM: optic tectum
Zebrafish Anatomy (ZA)	anatomical structure	1	0	--	INHERITED FROM: optic tectum || whole organism
Zebrafish Anatomy (ZA)	nervous system	0.2619	0.6911	Least Informative	INHERITED FROM: optic tectum
Zebrafish Anatomy (ZA)	multi-tissue structure	0.6912	0.6005	Least Informative	INHERITED FROM: optic tectum
Zebrafish Anatomy (ZA)	compound organ	0.8945	0.4571	Least Informative	INHERITED FROM: optic tectum
Zebrafish Anatomy (ZA)	central nervous system	0.2507	1.008	Moderately Informative	INHERITED FROM: optic tectum
Zebrafish Anatomy (ZA)	optic tectum	0.0009038	1.74	Informative	DIRECT

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Xenopus Anatomy (XA)

Highlighted in gray are those with FDR_all>0.001

	XA term	FDR (all)	IC level	SDXA level	Annotation (direct or inherited)
Xenopus ANatomical entity (XAN)	anatomical structure	0	0	--	DIRECT
Xenopus ANatomical entity (XAN)	anatomical group	0	0.1442	--	DIRECT
Xenopus ANatomical entity (XAN)	organism subdivision	0	0.1871	--	DIRECT
Xenopus ANatomical entity (XAN)	compound organ	0	0.24	--	DIRECT
Xenopus ANatomical entity (XAN)	anatomical region	0	0.193	--	DIRECT
Xenopus ANatomical entity (XAN)	multicellular anatomical structure	0	0.1217	--	DIRECT
Xenopus ANatomical entity (XAN)	whole organism	1	0.09747	--	INHERITED FROM: anatomical group || cavitated compound organ || multicellular anatomical structure || compound organ || anatomical region || organism subdivision
Xenopus ANatomical entity (XAN)	cavitated compound organ	0	0.3033	Least Informative	DIRECT
Xenopus DEvelopment stage (XDE)	prometamorphosis stage	0.0005075	2.663	--	DIRECT
Xenopus DEvelopment stage (XDE)	metamorphosing tadpole stage	0.4703	0.6715	--	INHERITED FROM: prometamorphosis stage
Xenopus DEvelopment stage (XDE)	tadpole stage	0.5749	0.5946	--	INHERITED FROM: prometamorphosis stage
Xenopus DEvelopment stage (XDE)	post-embryonic stage	0.5931	0.5693	Least Informative	INHERITED FROM: prometamorphosis stage

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Arabidopsis Plant Ontology (AP)

Highlighted in gray are those with FDR_all>0.001

	AP term	FDR (all)	IC level	SDAP level	Annotation (direct or inherited)
Plant ANatomical entity (PAN)	phyllome	0	0.3809	--	DIRECT
Plant ANatomical entity (PAN)	root	0	0.5579	--	DIRECT
Plant ANatomical entity (PAN)	shoot system	0	0.05747	--	DIRECT
Plant ANatomical entity (PAN)	plant organ	0	0.2816	--	DIRECT
Plant ANatomical entity (PAN)	sepal	0	0.5715	--	DIRECT
Plant ANatomical entity (PAN)	perianth	0	0.5448	--	DIRECT
Plant ANatomical entity (PAN)	calyx	0	0.5715	--	DIRECT
Plant ANatomical entity (PAN)	plant axis	0	0.3881	--	DIRECT
Plant ANatomical entity (PAN)	collective leaf structure	0	0.55	--	DIRECT
Plant ANatomical entity (PAN)	reproductive shoot system	0	0.4141	--	DIRECT
Plant ANatomical entity (PAN)	multi-tissue plant structure	0	0.2691	--	DIRECT
Plant ANatomical entity (PAN)	collective plant structure	0	0.01577	--	DIRECT
Plant ANatomical entity (PAN)	plant structure	1	0	--	INHERITED FROM: perianth || root || calyx || flower || collective plant structure || phyllome || multi-tissue plant structure || reproductive shoot system || collective leaf structure || shoot system || plant organ || root system || sepal || plant axis || collective phyllome structure
Plant ANatomical entity (PAN)	collective plant organ structure	1	0.04502	--	INHERITED FROM: calyx || flower || root system || root || perianth || phyllome || sepal || reproductive shoot system || collective phyllome structure || shoot system || collective leaf structure
Plant ANatomical entity (PAN)	flower	0	0.4337	Least Informative	DIRECT
Plant ANatomical entity (PAN)	collective phyllome structure	0	0.4648	Least Informative	DIRECT
Plant ANatomical entity (PAN)	root system	0	0.5346	Least Informative	DIRECT
Plant structure DEvelopment stage (PDE)	whole plant development stage	0	0.1968	--	DIRECT
Plant structure DEvelopment stage (PDE)	sporophyte vegetative stage	0	0.2036	--	DIRECT
Plant structure DEvelopment stage (PDE)	floral organ differentiation stage	0	0.0937	--	DIRECT
Plant structure DEvelopment stage (PDE)	corolla development stage	0	0.1981	--	DIRECT
Plant structure DEvelopment stage (PDE)	plant embryo stage	0	0.2833	--	DIRECT
Plant structure DEvelopment stage (PDE)	collective plant organ structure development stage	0	0.03771	--	DIRECT
Plant structure DEvelopment stage (PDE)	plant organ development stage	0	0.08108	--	DIRECT
Plant structure DEvelopment stage (PDE)	reproductive shoot system development stage	0	0.05008	--	DIRECT
Plant structure DEvelopment stage (PDE)	collective phyllome structure development stage	0	0.0937	--	DIRECT
Plant structure DEvelopment stage (PDE)	floral organ formation stage	0	0.0937	--	DIRECT
Plant structure DEvelopment stage (PDE)	flower development stage	1	0.07083	--	INHERITED FROM: corolla development stage || floral organ differentiation stage || floral organ formation stage
Plant structure DEvelopment stage (PDE)	life of whole plant stage	1	0.2022	--	INHERITED FROM: sporophyte vegetative stage || plant embryo stage
Plant structure DEvelopment stage (PDE)	shoot system development stage	1	0.04053	--	INHERITED FROM: reproductive shoot system development stage || floral organ formation stage || floral organ differentiation stage || corolla development stage || plant organ development stage
Plant structure DEvelopment stage (PDE)	sporophyte development stage	1	0.2022	--	INHERITED FROM: sporophyte vegetative stage || plant embryo stage

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Enzyme Commission (EC)

Highlighted in gray are those with FDR_all>0.001

	EC term	FDR (all)	IC level	SDEC level	Annotation (direct or inherited)
Enzyme Commission (EC)	Furin	0.000000000000009223	2.35	--	DIRECT
Enzyme Commission (EC)	Oryzin	0.000000000004783	2.651	--	DIRECT
Enzyme Commission (EC)	Proprotein convertase 2	0.000000000004783	2.475	--	DIRECT
Enzyme Commission (EC)	Subtilisin	0.0000000005762	2.651	--	DIRECT
Enzyme Commission (EC)	Proprotein convertase 1	0.000000002199	2.475	--	DIRECT
Enzyme Commission (EC)	Tripeptidyl-peptidase II	0.00000003945	2.651	--	DIRECT
Enzyme Commission (EC)	Tripeptidyl-peptidase I	0.00000009564	2.651	--	DIRECT
Enzyme Commission (EC)	Carboxypeptidase A	0.000114	2.952	--	DIRECT
Enzyme Commission (EC)	Hydrolases	0	0.3541	Least Informative	DIRECT
Enzyme Commission (EC)	Acting on peptide bonds (peptidases)	0	0.8949	Moderately Informative	DIRECT
Enzyme Commission (EC)	Serine endopeptidases	0.001555	1.35	Informative	INHERITED FROM: Oryzin || Furin || Proprotein convertase 2 || Subtilisin || Proprotein convertase 1
Enzyme Commission (EC)	Dipeptidyl-peptidases and tripeptidyl-peptidases	0	2.049	Highly Informative	DIRECT
Enzyme Commission (EC)	Metallocarboxypeptidases	0	2.049	Highly Informative	DIRECT

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InterPro annotation

• Cross references: IPR009020 SSF54897 Protein matches
• Abstract:

  Proteinase propeptide inhibitors (sometimes refered to as activation peptides) are responsible for the modulation of folding and activity of the pro-enzyme or zymogen. The pro-segment docks into the enzyme moiety shielding the substrate binding site, thereby promoting inhibition of the enzyme. Several such propeptides share a similar topology [12095256], despite often low sequence identities [9811547]. The propeptide region has an open-sandwich antiparallel-alpha/antiparallel-beta fold, with two alpha-helices and four beta-strands with a (beta/alpha/beta)x2 topology.

  This propeptide inhibitor domain occurs widely across all forms of life, and is found associated with the N-terminal region of a number of MEROPS peptidase families:

  • Metallopeptidase family M14A (carboxypeptidases).

  These include carboxypeptidase A1, A2 [9384570], A3, A4, A5, A6, U, insect gut carboxypeptidase and B [12162965].

  • Serine peptidase family S8A (subtilisin family). Members of this group belong to MEROPS inhibitor family I9, clan I-.
  • Serine peptidase family S8B (kexin family).

  The calcium-dependent serine peptidases belonging to MEROPS family S8B include the Kex2/subtilisin-like proprotein convertase (PC) family, which have been identified in all eukaryotes, these include furin, PC1/3, and PC2. The convertases are synthesised as an ¿inactive'' precursor proteins or zymogens. Following the N-terminal signal peptide is the prodomain, consisting of between 80 to 115 residues; it is an integral part of the zymogen and acts as a steric chaperone to aid proper folding of the zymogen. An autocatalytic cleavage at the second dibasic site, R-X-K-R, liberates the prodomain, but which remains attached and acts to inhibit any further endopeptidase activity by binding to the catalytic domain. Inhibition is released when the maturing convertase is transported to the trans-Golgi network (TGN) where a decrease in pH causes a second autoproteolytic cleavage to occur at the first dibasic site within the prodomain fragment [10842308].

InterPro database

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