Huntingtin-interacting protein 1 also known as HIP-1 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the HIP1 gene. Hip-1 is a protein that interacts with the

huntingtin Huntingtin (Htt) is the protein coded for in humans by the ''HTT'' gene, also known as the ''IT15'' ("interesting transcript 15") gene. Mutation, Mutated ''HTT'' is the cause of Huntington's disease (HD), and has been investigated for this role an ...

protein. It is known to contain a

domain A domain is a geographic area controlled by a single person or organization. Domain may also refer to: Law and human geography * Demesne, in English common law and other Medieval European contexts, lands directly managed by their holder rather ...

homologous to the death effector domains (DED) found on proteins involved in

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

. It is believed that accumulation of high levels of the free form of this protein (free as in dissociated from the huntingtin and free to bind other key protein(s)) in the cell is one of the mechanisms by which

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as di ...

is caused in

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...

(via the

caspase Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cyste ...

-3 route). The role of Hip-1 in caspase mediated cell death remains unclear.

Discovery

Huntingtin interacting protein 1 (HIP1) was first identified by Wanker et al. in 1997.

Function

HIP1 was found to bind to Htt in an N-terminal dependent manner, and co-localise with Htt in the CNS although the nature of this interaction with respect to was not identified. It has since been found that the CAG expansion seen with results in decreased binding affinity for HIP1, thus causing disruption of HIP1’s usual function, and also an increase in free HIP1. It is likely that this decreased affinity plays a role in mediating HD pathogenesis, due to loss of cytoskeletal integrity and induction of apoptosis. HIP1’s pro apoptotic effect may involve activation of caspase-8 and a novel HIP1 protein interactor HIPPI. HIP1’s non-pathological activity includes clathrin assembly via interaction with clathrin light chains. HIP1 is the human homologue of Sla2p, a membrane protein in the periphery. Sla2p is an actin-binding protein involved in endocytosis, thus indicating HIP1 in this role. Further details suggesting an important role for Hip-1 in endocytosis comes from binding studies looking at Hip-1 binding to actin. Actin binding by Hip-1 is altered depending on whether clathrin is also bound to Hip-1.

Clinical significance

HIP1 has also been found to be overexpressed in some cancers including a subset of colorectal and prostate cancers. This is of specific interest because prostate cancer disease progression involves altered transcription/expression of the androgen receptor (AR). The AR is a nuclear hormone receptor transcription factor that contains polyglutamine repeats. In 2005 Mills and colleagues showed that HIP1 is able to regulate transcription of hormone receptors via the androgen response element (ARE) and also alters the rate of degradation of the AR. It is likely that HIP1 is also able to regulate, or at least interact with proteins that also possess the ARE.

References

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