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Conserved domains on  [gi|12248390|dbj|BAB20094|]
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UCH-L3 [Mus musculus]

Protein Classification

ubiquitin carboxyl-terminal hydrolase( domain architecture ID 10176358)

ubiquitin carboxyl-terminal hydrolase is a C12 family peptidase that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin

CATH:  3.40.532.10
EC:  3.4.19.12
Gene Ontology:  GO:0004843|GO:0016579|GO:0006511
MEROPS:  C12
PubMed:  19489724
SCOP:  4000880

Graphical summary

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List of domain hits

 Name Accession Description Interval E-value
Peptidase_C12_UCH_L1_L3 cd09616
Cysteine peptidase C12 containing ubiquitin carboxyl-terminal hydrolase (UCH) families L1 and ...
 6-227 8.72e-143

Cysteine peptidase C12 containing ubiquitin carboxyl-terminal hydrolase (UCH) families L1 and L3; This ubiquitin C-terminal hydrolase (UCH) family includes UCH-L1 and UCH-L3, the two members sharing around 53% sequence identity as well as conserved catalytic residues. Both enzymes hydrolyze carboxyl terminal esters and amides of ubiquitin (Ub). UCH-L1, in dimeric form, has additional enzymatic activity as a ubiquitin ligase. It is highly abundant in the brain, constituting up to 2% of total protein, and is expressed exclusively in neurons and testes. Abnormal expression of UCH-L1 has been shown to correlate with several forms of cancer, including several primary lung tumors, lung tumor cell lines, and colorectal cancers. Mutations in the UCH-L1 gene have been linked to susceptibility to and protection from Parkinson's disease (PD); dysfunction of the hydrolase activity can lead to an accumulation of alpha-synuclein, which is linked to Parkinson's disease (PD), while accumulation of neurofibrillary tangles is linked to Alzheimer's disease (AD). UCH-L3 hydrolyzes isopeptide bonds at the C-terminal glycine of either Ub or Nedd8, a ubiquitin-like protein. It can also interact with Lys48-linked Ub dimers to protect them from degradation while inhibiting its hydrolase activity at the same time. Unlike UCH-L1, neither dimerization nor ligase activity have been observed for UCH-L3. It has been shown that levels of Nedd8 and the apoptotic protein p53 and Bax are elevated in UCH-L3 knockout mice upon cryptorchid injury, possibly contributing to profound germ cell loss via apoptosis.


:

Pssm-ID: 187737  Cd Length: 222  Bit Score: 397.78  E-value: 8.72e-143
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390   6 WLPLEANPEVTNQFLKQLGLHPNWQFVDVYGMEPELLSMVPRPVCAVLLLFPITEKYEVFRTEEEEKIKSQGQDVTSSVY 85
Cdd:cd09616   1 WIPLESNPEVMNKFLHKLGVSPGWEFVDVYGLDPELLAFVPRPVLAVLLLFPITKAYEEFRKEEEEEIKEKGQEVSESVY 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390  86 FMKQTISNACGTIGLIHAIANNKDKMHFESGSTLKKFLEESVSMSPEERAKFLENYDAIRVTHETSAHEGQTEAPSIDEK 165
Cdd:cd09616  81 FMKQTIGNACGTIALIHAVANNEDRINILEGSFLKKFLEEAKGLSPEERAKLLEKSEALEKAHAAAATEGQTEAPSADEK 160

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 12248390 166 VDLHFIALVHVDGHLYELDGRKPFPINHGKTSDETLLEDAIEVCKKFMERDPDELRFNAIAL 227
Cdd:cd09616 161 VNLHFIAFVKKDGHLYELDGRKPGPINHGPTSEETLLKDAAKVCRKFIEREPDEIRFSAIAL 222
 
Name Accession Description Interval E-value
Peptidase_C12_UCH_L1_L3 cd09616
Cysteine peptidase C12 containing ubiquitin carboxyl-terminal hydrolase (UCH) families L1 and ...
 6-227 8.72e-143

Cysteine peptidase C12 containing ubiquitin carboxyl-terminal hydrolase (UCH) families L1 and L3; This ubiquitin C-terminal hydrolase (UCH) family includes UCH-L1 and UCH-L3, the two members sharing around 53% sequence identity as well as conserved catalytic residues. Both enzymes hydrolyze carboxyl terminal esters and amides of ubiquitin (Ub). UCH-L1, in dimeric form, has additional enzymatic activity as a ubiquitin ligase. It is highly abundant in the brain, constituting up to 2% of total protein, and is expressed exclusively in neurons and testes. Abnormal expression of UCH-L1 has been shown to correlate with several forms of cancer, including several primary lung tumors, lung tumor cell lines, and colorectal cancers. Mutations in the UCH-L1 gene have been linked to susceptibility to and protection from Parkinson's disease (PD); dysfunction of the hydrolase activity can lead to an accumulation of alpha-synuclein, which is linked to Parkinson's disease (PD), while accumulation of neurofibrillary tangles is linked to Alzheimer's disease (AD). UCH-L3 hydrolyzes isopeptide bonds at the C-terminal glycine of either Ub or Nedd8, a ubiquitin-like protein. It can also interact with Lys48-linked Ub dimers to protect them from degradation while inhibiting its hydrolase activity at the same time. Unlike UCH-L1, neither dimerization nor ligase activity have been observed for UCH-L3. It has been shown that levels of Nedd8 and the apoptotic protein p53 and Bax are elevated in UCH-L3 knockout mice upon cryptorchid injury, possibly contributing to profound germ cell loss via apoptosis.


Pssm-ID: 187737  Cd Length: 222  Bit Score: 397.78  E-value: 8.72e-143
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390   6 WLPLEANPEVTNQFLKQLGLHPNWQFVDVYGMEPELLSMVPRPVCAVLLLFPITEKYEVFRTEEEEKIKSQGQDVTSSVY 85
Cdd:cd09616   1 WIPLESNPEVMNKFLHKLGVSPGWEFVDVYGLDPELLAFVPRPVLAVLLLFPITKAYEEFRKEEEEEIKEKGQEVSESVY 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390  86 FMKQTISNACGTIGLIHAIANNKDKMHFESGSTLKKFLEESVSMSPEERAKFLENYDAIRVTHETSAHEGQTEAPSIDEK 165
Cdd:cd09616  81 FMKQTIGNACGTIALIHAVANNEDRINILEGSFLKKFLEEAKGLSPEERAKLLEKSEALEKAHAAAATEGQTEAPSADEK 160

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 12248390 166 VDLHFIALVHVDGHLYELDGRKPFPINHGKTSDETLLEDAIEVCKKFMERDPDELRFNAIAL 227
Cdd:cd09616 161 VNLHFIAFVKKDGHLYELDGRKPGPINHGPTSEETLLKDAAKVCRKFIEREPDEIRFSAIAL 222
Peptidase_C12 pfam01088
Ubiquitin carboxyl-terminal hydrolase, family 1;
7-214 1.60e-108

Ubiquitin carboxyl-terminal hydrolase, family 1;


Pssm-ID: 460057  Cd Length: 205  Bit Score: 310.61  E-value: 1.60e-108
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390     7 LPLEANPEVTNQFLKQLGLHPNWQFVDVYGM-EPELLSMVPRPVCAVLLLFPITEKYEVFRTEEEEKIKSQGQDVtssvY 85
Cdd:pfam01088   1 IPLESNPEVFTELLHKLGVSGVLQFEDVYSLdDEELLAMLPRPVYALIFLFPITEAYEEKREEEGEEIKDEGENV----F 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390    86 FMKQTISNACGTIGLIHAIANNKDkMHFESGSTLKKFLEESVSMSPEERAKFLENYDAIRVTHETSAHEGQTEAPSIDEK 165
Cdd:pfam01088  77 FAKQTIGNACGTIALLHALLNNPD-IPLDLGSTLKKFKEFTKGLSPEERGEALENSEELREAHNSFARQGQTEAPSDDDD 155

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|
gi 12248390   166 VDLHFIALVHVDGHLYELDGRKPFPINHGKTSDETLLEDA-IEVCKKFME 214
Cdd:pfam01088 156 VDFHFIAFVPVDGHLYELDGLKPGPIDHGPCSDEDWLLDAvRKVIQERIE 205
 
Name Accession Description Interval E-value
Peptidase_C12_UCH_L1_L3 cd09616
Cysteine peptidase C12 containing ubiquitin carboxyl-terminal hydrolase (UCH) families L1 and ...
 6-227 8.72e-143

Cysteine peptidase C12 containing ubiquitin carboxyl-terminal hydrolase (UCH) families L1 and L3; This ubiquitin C-terminal hydrolase (UCH) family includes UCH-L1 and UCH-L3, the two members sharing around 53% sequence identity as well as conserved catalytic residues. Both enzymes hydrolyze carboxyl terminal esters and amides of ubiquitin (Ub). UCH-L1, in dimeric form, has additional enzymatic activity as a ubiquitin ligase. It is highly abundant in the brain, constituting up to 2% of total protein, and is expressed exclusively in neurons and testes. Abnormal expression of UCH-L1 has been shown to correlate with several forms of cancer, including several primary lung tumors, lung tumor cell lines, and colorectal cancers. Mutations in the UCH-L1 gene have been linked to susceptibility to and protection from Parkinson's disease (PD); dysfunction of the hydrolase activity can lead to an accumulation of alpha-synuclein, which is linked to Parkinson's disease (PD), while accumulation of neurofibrillary tangles is linked to Alzheimer's disease (AD). UCH-L3 hydrolyzes isopeptide bonds at the C-terminal glycine of either Ub or Nedd8, a ubiquitin-like protein. It can also interact with Lys48-linked Ub dimers to protect them from degradation while inhibiting its hydrolase activity at the same time. Unlike UCH-L1, neither dimerization nor ligase activity have been observed for UCH-L3. It has been shown that levels of Nedd8 and the apoptotic protein p53 and Bax are elevated in UCH-L3 knockout mice upon cryptorchid injury, possibly contributing to profound germ cell loss via apoptosis.


Pssm-ID: 187737  Cd Length: 222  Bit Score: 397.78  E-value: 8.72e-143
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390   6 WLPLEANPEVTNQFLKQLGLHPNWQFVDVYGMEPELLSMVPRPVCAVLLLFPITEKYEVFRTEEEEKIKSQGQDVTSSVY 85
Cdd:cd09616   1 WIPLESNPEVMNKFLHKLGVSPGWEFVDVYGLDPELLAFVPRPVLAVLLLFPITKAYEEFRKEEEEEIKEKGQEVSESVY 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390  86 FMKQTISNACGTIGLIHAIANNKDKMHFESGSTLKKFLEESVSMSPEERAKFLENYDAIRVTHETSAHEGQTEAPSIDEK 165
Cdd:cd09616  81 FMKQTIGNACGTIALIHAVANNEDRINILEGSFLKKFLEEAKGLSPEERAKLLEKSEALEKAHAAAATEGQTEAPSADEK 160

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 12248390 166 VDLHFIALVHVDGHLYELDGRKPFPINHGKTSDETLLEDAIEVCKKFMERDPDELRFNAIAL 227
Cdd:cd09616 161 VNLHFIAFVKKDGHLYELDGRKPGPINHGPTSEETLLKDAAKVCRKFIEREPDEIRFSAIAL 222
Peptidase_C12 pfam01088
Ubiquitin carboxyl-terminal hydrolase, family 1;
7-214 1.60e-108

Ubiquitin carboxyl-terminal hydrolase, family 1;


Pssm-ID: 460057  Cd Length: 205  Bit Score: 310.61  E-value: 1.60e-108
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390     7 LPLEANPEVTNQFLKQLGLHPNWQFVDVYGM-EPELLSMVPRPVCAVLLLFPITEKYEVFRTEEEEKIKSQGQDVtssvY 85
Cdd:pfam01088   1 IPLESNPEVFTELLHKLGVSGVLQFEDVYSLdDEELLAMLPRPVYALIFLFPITEAYEEKREEEGEEIKDEGENV----F 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390    86 FMKQTISNACGTIGLIHAIANNKDkMHFESGSTLKKFLEESVSMSPEERAKFLENYDAIRVTHETSAHEGQTEAPSIDEK 165
Cdd:pfam01088  77 FAKQTIGNACGTIALLHALLNNPD-IPLDLGSTLKKFKEFTKGLSPEERGEALENSEELREAHNSFARQGQTEAPSDDDD 155

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|
gi 12248390   166 VDLHFIALVHVDGHLYELDGRKPFPINHGKTSDETLLEDA-IEVCKKFME 214
Cdd:pfam01088 156 VDFHFIAFVPVDGHLYELDGLKPGPIDHGPCSDEDWLLDAvRKVIQERIE 205
Peptidase_C12_UCH37_BAP1 cd09617
Cysteine peptidase C12 containing ubiquitin carboxyl-terminal hydrolase (UCH) families UCH37 ...
 6-227 2.22e-32

Cysteine peptidase C12 containing ubiquitin carboxyl-terminal hydrolase (UCH) families UCH37 (UCH-L5) and BAP1; This ubiquitin C-terminal hydrolase (UCH) family includes UCH37 (also known as UCH-L5) and BRCA1-associated protein-1 (BAP1). They contain a UCH catalytic domain as well as an additional C-terminal extension which plays a role in protein-protein interactions. UCH37 is responsible for ubiquitin (Ub) isopeptidase activity in the 19S proteasome regulatory complex; it disassembles Lys48-linked poly-ubiquitin from the distal end of the chain. It is also associated with the human Ino80 chromatin-remodeling complex (hINO80) in the nucleus and can be activated through transient association of hINO80 with hRpn13 that is bound to the 19S regulatory particle or the proteasome. UCH37 possibly plays a role in oncogenesis; it competes with Smad ubiquitination regulatory factor 2 (Smurf2, ubiquitin ligase) in binding concurrently to Smad7 in order to deubiquitinate the activated type I transforming growth factor beta (TGF-beta) receptor, thus rescuing it from proteasomal degradation. BAP1 binds to the wild-type BRCA1 RING finger domain, localized in the nucleus. In addition to the UCH catalytic domain, BAP1 contains a UCH37-like domain (ULD), binding domains for BRCA1 and BARD1, which form a tumor suppressor heterodimeric complex, and a binding domain for HCFC1, which interacts with histone-modifying complexes during cell division. The full-length human BRCA1 is a ubiquitin ligase. However, BAP1 does not appear to function in the deubiquitination of autoubiquitinated BRCA1. BAP1 exhibits tumor suppressor activity in cancer cells, and gene mutations have been reported in a small number of breast and lung cancer samples. In metastasis of uveal melanoma, the most common primary cancer of the eye, inactivating somatic mutations have been identified in the gene encoding BAP1 on chromosome 3p21.1. These mutations include several that cause premature protein termination as well as affect its UCH domain, thus implicating loss of BAP1 and suggesting that the BAP1 pathway may be a valuable therapeutic target.


Pssm-ID: 187738  Cd Length: 219  Bit Score: 116.96  E-value: 2.22e-32
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390   6 WLPLEANPEVTNQFLKQLGLHpNWQFVDVYGMEPELLSMVPrPVCAVLLLFpiteKYEVFRTEEEEKIKsqgQDVTSSVY 85
Cdd:cd09617   1 WCEIESDPGVFTELLEEFGVK-GVQVEELYSLDADSLEQLP-PVYGLIFLF----KWQEGEEDEGSVVD---DEIPSNIF 71

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390  86 FMKQTISNACGTIGLIHAIANNKDKMHFesGSTLKKFLEESVSMSPEERAKFLENYDAIRVTHETSA----HEGQTEAPS 161
Cdd:cd09617  72 FANQVIPNACATQALLSVLLNCSDEVDL--GETLSEFKEFTKGFDPEMKGEAIGNSEEIRKVHNSFArpepFLLDEKLNK 149

                       170       180       190       200       210       220       230
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390 162 IDEKVDL--HFIALVHVDGHLYELDGRKPFPINHGKTSD-ETLLEDAIEVCKKFMER-DPDELRFNAIAL 227
Cdd:cd09617 150 KATKEEDafHFISYVPIGGRLYELDGLKEGPIDHGPCSEgEDWLEKARPVIQARIARySEGEIRFNLMAV 219
Peptidase_C12 cd02255
Cysteine peptidase C12 contains ubiquitin carboxyl-terminal hydrolase (UCH) families L1, L3, ...
 6-227 1.31e-25

Cysteine peptidase C12 contains ubiquitin carboxyl-terminal hydrolase (UCH) families L1, L3, L5 and BAP1; The ubiquitin C-terminal hydrolase (UCH; ubiquitinyl hydrolase; ubiquitin thiolesterase) family of deubiquitinating enzymes (DUBs) consists of four members to date: UCH-L1, UCH-L3, UCH-L5 (UCH37) and BRCA1-associated protein-1 (BAP1), all containing a conserved catalytic domain with cysteine peptidase activity. UCH-L1 hydrolyzes carboxyl terminal esters and amides of ubiquitin (Ub). Dysfunction of this hydrolase activity can lead to an accumulation of alpha-synuclein, which is linked to Parkinson's disease (PD) and neurofibrillary tangles, linked to Alzheimer's disease (AD). UCH-L1, in its dimeric form, has additional enzymatic activity as a ubiquitin ligase. UCH-L3 hydrolyzes isopeptide bonds at the C-terminal glycine of either Ub or Nedd8, a ubiquitin-like protein. UCH-L3 can also interact with Lys48-linked Ub dimers to protect it from degradation while inhibiting its hydrolase activity at the same time. UCH-L1 and UCH-L3 are the most closely related of the UCH members. UCH-L5 (UCH37) is involved in the deubiquitinating activity in the 19S proteasome regulatory complex. It is also associated with the human Ino80 chromatin-remodeling complex (hINO80) in the nucleus. BAP1 binds to the wild-type BRCA1 RING finger domain, localized in the nucleus. It consists of the N-terminal UCH domain and two predicted nuclear localization signals (NLSs), only one of which is functional. The full-length human BRCA1 is a ubiquitin ligase. However, BAP1 does not appear to function in the deubiquitination of autoubiquitinated BRCA1. There is growing evidence that UCH enzymes and human malignancies are closely correlated. Studies show that UCH enzymes play a crucial role in some signaling pathways and in cell-cycle regulation.


Pssm-ID: 187736  Cd Length: 222  Bit Score: 99.47  E-value: 1.31e-25
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390   6 WLPLEANPEVTNQFLKQLGLHPNWQFVDVYGMEPELLSMVPRPVCAVLLLFPITEKYEVFRTEEEEKIKSQGQDVTSSVY 85
Cdd:cd02255   1 WLPLEANPEVTNQFLKQLGLHPNWQFVDVYGMDPELLSMVPRPVCAVLLLFPITEKYEVFRTEEEEKIKSQGQDVTSSVY 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 12248390  86 FMKQTISNACGTIGLIHAIAN--NKDKMHFesGSTLKKFLEESVSMSPEERAKFLENYDAIRVTHETSAHEGQTEAPSID 163
Cdd:cd02255  81 FMKQTISNACGTIGLIHAIANnkDKMHFES--GSTLKKFLEESVSMSPEERARYLENYDAIRVTHETSAHEGQTEAPSID 158

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 12248390 164 EKVDLHFIALVHVDGHLYELDGRKPFPINHGKTSDETLLEDAIEVCKKFMERDPDELRFNAIAL 227
Cdd:cd02255 159 EKVDLHFIALVHVDGHLYELDGRKPFPINHGETSDETLLEDAIEVCKKFMERDPDELRFNAIAL 222
 
Blast search parameters
Data Source: Precalculated data, version = cdd.v.3.21
Preset Options:Database: CDSEARCH/cdd   Low complexity filter: no  Composition Based Adjustment: yes   E-value threshold: 0.01

References:

  • Wang J et al. (2023), "The conserved domain database in 2023", Nucleic Acids Res.51(D)384-8.
  • Lu S et al. (2020), "The conserved domain database in 2020", Nucleic Acids Res.48(D)265-8.
  • Marchler-Bauer A et al. (2017), "CDD/SPARCLE: functional classification of proteins via subfamily domain architectures.", Nucleic Acids Res.45(D)200-3.
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