Protein interactions DISC1

1 protein interactions

1.1 disc1
1.2 atf4/atf5
1.3 fez1
1.4 kalirin-7
1.5 map1a
1.6 ndel1/nudel
1.7 pcm1/pericentriolar material

protein interactions

the disc1 protein has no known enzymatic activity; rather exerts effect on multiple proteins through interactions modulate functional states , biological activities in time , space. these include:

disc1

disc1 has been shown self-associate, form dimers, multimers, , oligomers. ability of disc1 form complexes may important in regulating affinity interacting partners such ndel1. in postmortem brain samples of schizophrenia patients there increase in insoluble disc1 oligomer aggregates, indicative of common link other neurological disorders characterised protein aggregation, namely alzheimer s disease, parkinson s disease, , huntington s disease.

atf4/atf5

atf4 , atf5 members of leucine zipper activating transcription factor / creb family. known bind , regulate function of gabab receptors in synapses , involved in signal transduction cell membrane nucleus. both proteins interact disc1 , gabab receptors via second c-terminal leucine zipper domain, therefore disc1 able regulate gabab receptor function through interaction atf4/atf5.

fez1

disc1 participates in neurite outgrowth through interaction fasciculation , elongation protein ζ-1 (fez1). fez1 mammalian homolog of c. elegans unc-76 protein involved in axonal outgrowth , fasciculation. c-terminal region of fez1 (aa 247-392) required interaction disc1. disc1 region (aa 446-633), containing 2 stretches coiled-coil-forming potential critical interaction fez1. disc1-fez1 interaction enhanced during neuro-differentiation, , expression of fez1-binding domain of disc1 has dominant negative effect on neurite outgrowth, implies co-operation of disc1 , fez1 in process.

kalirin-7

the disc1 protein plays role in process of regulating spine form , function through interactions kalirin-7 (kal-7). kal-7 regulator of spine morphology , synaptic plasticity in association neuronal activity. kal-7-dependent regulation of spine formation occurs through activity gdp/gtp exchange factor rac1. activation of rac1 kal-7 leads increased spine size , synaptic strength through regulation of actin cytoskeleton rac1. disc1 able bind kal-7, confining access rac1, , in turn regulate spinal formation. activation of nmda receptors causes dissociation of disc1 , kal-7, leaving kal-7 available activate rac1.

map1a

disc1 shows strong interaction microtubule-associated protein map1a controls polymerization , stabilization of microtubule networks in neurons, , thereby influence cell shape , intracellular transport of vesicles , organelles. map1a binds far n-terminus (aa 293-696) of disc1, , amino terminus of disc1 binds lc2 subunit of map1a. lc2 subunit of map1a contains actin-binding domain , necessary , sufficient microtubule binding , polymerization, therefore disc1 able regulate ability of map1a polymerize , stabilize microtubules , traffic proteins correct localization in synaptic architecture.

ndel1/nudel

disc1 localized centrosome, primary microtubule organizing center of cell, via interaction nuclear distribution gene homologue-like 1 (ndel1, called nudel), part of protein complex involved in cytoskeletal processes of neuronal migration, including nucleokinesis , neurite outgrowth. nudel known play role in axon regeneration , has additional disc1-modulated function cysteine endopeptidase. localization of nudel axons dependent on expression of disc1. nudel binds 100 amino acid domain of disc1 (aa 598-697) containing coiled coil domain , leucine zipper. amino acid domain of nudel binds disc1 carboxyl terminal 100 amino acids of protein (aa 241-345), contains cytoplasmic dynein binding site.

pcm1/pericentriolar material

the protein pericentriolar material 1 (pcm1) associated cilia development in cns interacts directly disrupted-in-schizophrenia 1 (disc1) , calmodulin 1 (calm1)proteins. kamiya et al. have shown pcm1, disc1 , bbs4 can disrupt neuronal organisation in mouse when expression down-regulated. markers @ pericentriolar material 1 gene (pcm1) have shown genetic association schizophrenia in several schizophrenia case control studies. resequencing of genomic dna research volunteers had inherited haplotypes associated schizophrenia showed threonine isoleucine mis-sense mutation in exon 24 may change structure , function of pcm1 (rs370429). mutation found heterozygote in ninety 8 schizophrenic research subjects , controls out of total sample of 2,246 case , control research subjects. amongst ninety 8 carriers of rs370429 sixty 7 affected schizophrenia. same alleles , haplotypes associated schizophrenia in both london , aberdeen samples. potential aetiological base pair change in pcm1 rs445422 altered splice site signal. further mutation, rs208747, shown electrophoretic mobility shift assays create or destroy promoter transcription factor site. 5 further non-synonymous changes in exons found. given number , identity of haplotypes associated schizophrenia further aetiological base pair changes must exist within , around pcm1 gene. findings in relation pcm1 support role of disc1 being susceptibility locus schizophrenia.

other interactions include: actn2, cep63, eif3a, ranbp9, , sptbn4.