Disease relevance of CLINT1

• In renal insufficiency patients, t1/2 was prolonged to 25 hr, fup increased to 7%, and Cmax,u and Clint were unchanged [1].
• Schizophrenia (SCZD) or schizoaffective disorders are quite common features in patients with DiGeorge/velo-cardio-facial syndrome (DGS/VCFS) as a result of chromosome 22q11.2 aploinsufficiency [2].

High impact information on CLINT1

• Adaptors, scaffolds, BAR-domain and ENTH-domain proteins all must be coordinated to carry out this sequence of events prior to the action of dynamin [3].
• Recently, phosphoinositides have been found to direct the localization and activity of effector proteins containing consensus sequence motifs such as FYVE, PH and ENTH domains [4].
• Now, recent studies have identified novel ENTH/ANTH proteins that participate in CCV-mediated traffic between the trans-Golgi Network (TGN) and endosomes and have defined a molecular basis for interaction with AP-1 and GGA adaptors in clathrin coats of the TGN/endosomes [5].
• Key to endocytic CCV formation are proteins containing related phosphoinositide-binding ENTH and ANTH domains [5].
• Membrane recruitment of these peripheral proteins is mediated by a growing number of modular membrane-targeting domains, including C1, C2, PH, FYVE, PX, ENTH, ANTH, BAR, FERM, and tubby domains, that recognize specific lipid molecules in the membranes [6].

Biological context of CLINT1

• Our experiments identified the first cytoplasmic protein binding to specific ENTH domains [7].
• Among the ten novel proteins identified is the rat homologue of a predicted gene product from human, mouse, and Drosophila genomics projects, which we named enthoprotin [8].
• A genetically determined abnormality in the structure, function, or expression of enthoprotin is likely to be responsible for genetic susceptibility to a subtype of schizophrenia on chromosome 5q33.3 [9].
• Four adjacent markers at the 5' end of the Epsin 4 gene showed significant evidence of linkage disequilibrium with schizophrenia [9].
• These included two microsatellite markers, D5S1403 (P=.01) and AAAT11 (P=.009), and two single-nucleotide-polymorphism markers within the Epsin 4 gene, rs10046055 (P=.007) and rs254664 (P=.01) [9].

Anatomical context of CLINT1

• ENTH proteins are involved in the formation of clathrin-coated vesicles [7].
• Specific interaction between SNAREs and epsin N-terminal homology (ENTH) domains of epsin-related proteins in trans-Golgi network to endosome transport [7].
• Moreover, although epsinR binds AP-1 via its COOH-terminal domain, its NH(2)-terminal ENTH domain can be independently recruited onto membranes, both in vivo and in vitro [10].
• Brefeldin A causes epsinR to redistribute into the cytosol, and recruitment of the ENTH domain requires GTPgammaS, indicating that membrane association is ARF dependent [10].
• Both proteins interact with clathrin and the AP2 adaptor complex and also bind to the phosphoinositide-containing plasma membrane via an epsin/AP180 N-terminal homology (ENTH/ANTH) domain [11].

Associations of CLINT1 with chemical compounds

• In contrast to other ENTH domain-containing proteins, lipid binding is preferential to the 3-phosphate-containing inositol lipids, phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,5-bisphosphate [12].
• In protein-lipid overlay assays, the epsinR ENTH domain binds to PtdIns(4)P, suggesting a possible mechanism for ARF-dependent recruitment onto TGN membranes [10].
• A notable feature of Clint is a carboxyl-terminal methionine-rich domain (Met(427)-Met(605)), which contains >17% methionine [13].
• EpsinR was also involved in retrograde transport of two endogenous proteins, TGN38/46 and mannose 6-phosphate receptor [14].
• Epsin 1 and 2 are most similar in their NH(2)-terminal region, which represents a module (epsin NH(2) terminal homology domain, ENTH domain) found in a variety of other proteins of the data base [15].

Enzymatic interactions of CLINT1

• Total Clint values of hydroxy and sulfone metabolite formation catalyzed by all these p450 enzymes were consistently higher for S-lansoprazole than for the R-form [16].

Other interactions of CLINT1

• Solution structure of the epsin N-terminal homology (ENTH) domain of human epsin [17].
• The amino terminus exhibits multiple copies of leucine-rich nuclear transport signals followed by ENTH, DUF28, and SEC1 homology domains [18].
• Pleckstrin homology domains, FYVE domains, PX domains, ENTH domains, CALM domains, PDZ domains, PTB domains and FERM domains are all inositide-recognition modules [19].
• The ENTH domain is a newly found PtdIns(4,5)P2 binding unit conserved among endocytic proteins like epsins, AP180, and the Hip1/Sla2 family [20].
• The decreased plasma and tissue binding and lower Clint suggest that, in the treatment of azotemic patients with rheumatoid arthritis, the dose of oxaprozin should begin at 600 mg once a day [21].

References