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kalirin; huntingtin-associated protein-interacting protein; protein duo; serine/threonine protein kinase with Dbl- & pleckstrin homology domain (KALRN, DUET, DUO, HAPIP, TRAD)

Function: - promotes the exchange of GDP by GTP - activates specific Rho GTPase family members, thereby inducing various signaling mechanisms that regulateneuronal shape, growth, & plasticity, through effects on the actin cytoskeleton - induces lamellipodia independent of its GEF activity - autophosphorylated - interacts with the C-terminal of peptidylglycine alpha-amidating monooxygenase (PAM) & with the huntingtin-associated protein 1 (HAP1) (putative) Cofactor: Mg+2 Structure: - the two GEF domains catalyze nucleotide exchange for RAC1 & RhoA which are bound by DH1 & DH2 respectively - the two GEF domains appear to play differing roles in neuronal development & axonal outgrowth - SH3 1 binds to the first GEF domain inhibiting GEF activity only when in the presence of a PXXP peptide,suggesting that the SH3 domain/peptide interaction mediates binding to GEF1 - CRK1 SH3 domain binds to & inhibits GEF1 activity (putative) - belongs to the protein kinase superfamily, CAMK Ser/Thr protein kinase family - contains 1 CRAL-TRIO domain - contains 2 DH (DBL-homology) domains - contains 1 fibronectin F3 module - contains 1 Ig-like C2-type domain (immunoglobulin-like) - contains 2 PH domains - contains 1 protein kinase domain - contains 2 SH3 domains - contains 5 spectrin repeats Compartment: - cytoplasm, cytoskeleton Alternative splicing: Alternative initiation; named isoforms=6 Expression: - isoform 2 is brain specific, highly expressed in cerebral cortex, putamen, amygdala, hippocampus & caudate nucleus - weakly expressed in brain stem & cerebellum - isoform 4 is expressed in skeletal muscle Pathology: - genetic variation in KALRN is associated with susceptibility to coronary heart disease type 5 - neurofibrillary tangle burden & kalirin-mediated synaptic dysfunction may be neuropathologic components of psychosis in Alzheimer's disease Notes: - called DUO because the encoded protein is closely related to but shorter than TRIO

General

guanine nucleotide exchange factor (GDP/GTP dissociation stimulator, guanine nucleotide-releasing factor/protein, GNEF, GNDS, GDS) serine/threonine kinase

Properties

SIZE: entity length = 2985 aa MW = 340 kD COMPARTMENT: cytoplasm MOTIF: CRAL-TRIO lipid binding domain {35-180} spectrin repeat {188-308} spectrin repeat {310-416} spectrin repeat {536-642} glutamine-rich region {682-687} MOTIF: glutamine residue (SEVERAL) spectrin repeat {890-1004} spectrin repeat {1130-1222} DH 1 {1281-1456} PH domain {1468-1580} src homology 3 [SH3] domain SITE: 1646-1711 Ser phosphorylation site {S1750} Ser phosphorylation site {S1753} Ser phosphorylation site {S1756} Ser phosphorylation site {S1773} Ser phosphorylation site {S1799} Ser phosphorylation site {S1817} DH 2 {1928-2103} PH domain {2115-2225} Ser phosphorylation site {S2236} Ser phosphorylation site {S2261} src homology 3 [SH3] domain SITE: 2320-2385 immunoglobulin superfamily domain {2470-2563} MOTIF: cysteine residue {C2491} MODIFICATION: cysteine residue {C2547} cysteine residue {C2547} MODIFICATION: cysteine residue {C2491} fibronectin type III domain or F3 module {2568-2659} kinase domain SITE: 2683-2937 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 2689-2697 ATP-binding site NAME: ATP-binding site SITE: 2712-2712 aspartate residue {D2802} STATE: active state

Database Correlations

OMIM correlations MORBIDMAP 604605 UniProt O60229 PFAM correlations Entrez Gene 8997 Kegg hsa:8997 ENZYME 2.7.11.1

References

  1. UniProt :accession O60229
  2. Entrez Gene :accession 8997
  3. Ismail Z, Creese B, Aarsland D et al Psychosis in Alzheimer disease - mechanisms, genetics and therapeutic opportunities. Nat Rev Neurol 2022. January 4. PMID: 34983978 Review. https://www.nature.com/articles/s41582-021-00597-3