Target Information
| Target General Information | Top | |||||
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| Target ID |
T17367
(Former ID: TTDI02182)
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| Target Name |
Sequestosome-1 p62 (SQSTM1)
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| Synonyms |
Ubiquitin-binding protein p62; Sequestosome-1; Phosphotyrosine-independent ligand for the Lck SH2 domain of 62kDa; Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa; OSIL; ORCA; EBIAP; EBI3-associated protein of 60 kDa
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| Gene Name |
SQSTM1
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| Target Type |
Literature-reported target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Nasopharyngitis [ICD-11: CA00] | |||||
| Function |
Functions as a bridge between polyubiquitinated cargo and autophagosomes. Interacts directly with both the cargo to become degraded and an autophagy modifier of the MAP1 LC3 family. Along with WDFY3, involved in the formation and autophagic degradation of cytoplasmic ubiquitin-containing inclusions (p62 bodies, ALIS/aggresome-like induced structures). Along with WDFY3, required to recruit ubiquitinated proteins to PML bodies in the nucleus. May regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. Adapter that mediates the interaction between TRAF6 and CYLD. May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels. Involved in endosome organization by retaining vesicles in the perinuclear cloud: following ubiquitination by RNF26, attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport. Promotes relocalization of 'Lys-63'-linked ubiquitinated TMEM173/STING to autophagosomes. Autophagy receptor required for selective macroautophagy (aggrephagy).
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| BioChemical Class |
Zinc-finger
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| UniProt ID | ||||||
| Sequence |
MASLTVKAYLLGKEDAAREIRRFSFCCSPEPEAEAEAAAGPGPCERLLSRVAALFPALRP
GGFQAHYRDEDGDLVAFSSDEELTMAMSYVKDDIFRIYIKEKKECRRDHRPPCAQEAPRN MVHPNVICDGCNGPVVGTRYKCSVCPDYDLCSVCEGKGLHRGHTKLAFPSPFGHLSEGFS HSRWLRKVKHGHFGWPGWEMGPPGNWSPRPPRAGEARPGPTAESASGPSEDPSVNFLKNV GESVAAALSPLGIEVDIDVEHGGKRSRLTPVSPESSSTEEKSSSQPSSCCSDPSKPGGNV EGATQSLAEQMRKIALESEGRPEEQMESDNCSGGDDDWTHLSSKEVDPSTGELQSLQMPE SEGPSSLDPSQEGPTGLKEAALYPHLPPEADPRLIESLSQMLSMGFSDEGGWLTRLLQTK NYDIGAALDTIQYSKHPPPL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | IMX-942 | Drug Info | Preclinical | Mucositis | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Regulator (upregulator) | [+] 1 Regulator (upregulator) drugs | + | ||||
| 1 | IMX-942 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Arginine | Ligand Info | |||||
| Structure Description | Crystal structure of p62 ZZ domain in complex with free arginine | PDB:6MJ7 | ||||
| Method | X-ray diffraction | Resolution | 1.41 Å | Mutation | No | [3] |
| PDB Sequence |
GSNMVHPNVI
127 CDGCNGPVVG137 TRYKCSVCPD147 YDLCSVCEGK157 GLHRGHTKLA167 FPSP |
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Mitophagy - animal | hsa04137 | Affiliated Target |
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| Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy | ||
| Autophagy - animal | hsa04140 | Affiliated Target |
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| Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy | ||
| Necroptosis | hsa04217 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Cellular senescence | hsa04218 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Osteoclast differentiation | hsa04380 | Affiliated Target |
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| Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
| Degree | 36 | Degree centrality | 3.87E-03 | Betweenness centrality | 2.61E-03 |
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| Closeness centrality | 2.51E-01 | Radiality | 1.44E+01 | Clustering coefficient | 1.32E-01 |
| Neighborhood connectivity | 3.94E+01 | Topological coefficient | 5.26E-02 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Osteoclast differentiation | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | EGFR1 Signaling Pathway | |||||
| PID Pathway | [+] 4 PID Pathways | + | ||||
| 1 | IL1-mediated signaling events | |||||
| 2 | TNF receptor signaling pathway | |||||
| 3 | p75(NTR)-mediated signaling | |||||
| 4 | Neurotrophic factor-mediated Trk receptor signaling | |||||
| Reactome | [+] 4 Reactome Pathways | + | ||||
| 1 | NRIF signals cell death from the nucleus | |||||
| 2 | p75NTR recruits signalling complexes | |||||
| 3 | NF-kB is activated and signals survival | |||||
| 4 | Interleukin-1 signaling | |||||
| WikiPathways | [+] 10 WikiPathways | + | ||||
| 1 | Senescence and Autophagy in Cancer | |||||
| 2 | NRF2 pathway | |||||
| 3 | Nuclear Receptors Meta-Pathway | |||||
| 4 | Apoptosis-related network due to altered Notch3 in ovarian cancer | |||||
| 5 | BDNF signaling pathway | |||||
| 6 | RANKL/RANK Signaling Pathway | |||||
| 7 | Signalling by NGF | |||||
| 8 | IL-1 signaling pathway | |||||
| 9 | Interleukin-1 signaling | |||||
| 10 | Regulation of toll-like receptor signaling pathway | |||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of SARomics Biostructures. | |||||
| REF 2 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018500) | |||||
| REF 3 | ZZ-dependent regulation of p62/SQSTM1 in autophagy. Nat Commun. 2018 Oct 22;9(1):4373. | |||||
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