CDK5 regulatory subunit-associated protein 2 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 ''CDK5RAP2''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. It has necessary roles in the formation and stability of

microtubules Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...

from the

centrosome In cell biology, the centrosome (Latin centrum 'center' + Greek sōma 'body') (archaically cytocentre) is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell, as well as a regulator of cell-cycle progre ...

and has been found to be linked to human brain size variation in males. Multiple transcript variants exist for this gene, but the full-length nature of only two has been determined. CDK5RAP2 is homologous to the ''

Drosophila ''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...

'' protein centrosomin (cnn) and paralogous to

myomegalin Myomegalin, also known as phosphodiesterase 4D-interacting protein or cardiomyopathy-associated protein 2, is a protein that in humans is encoded by the ''PDE4DIP'' gene. It has roles in the Microtubule nucleation, formation of microtubules from ...

, which in mammals contains an

Olduvai domain The Olduvai domain, known until 2018 as DUF1220 (domain of unknown function 1220) and the NBPF repeat, is a protein domain that shows a striking human lineage-specific (HLS) increase in copy number and appears to be involved in human brain evolu ...

, a domain implicated in human brain size evolution.

Function

CDK5RAP2 is necessary for the proper formation, anchoring and orientation of

from the

. It binds with the γ-tubulin ring

complex Complex commonly refers to: * Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe ** Complex system, a system composed of many components which may interact with each ...

(γTuRC), and this is required for the γTuRC to attach to the centrosome. CDK5RAP2 also binds to p25, a form of

CDK5R1 Cyclin-dependent kinase 5 activator 1 is an enzyme that in humans is encoded by the ''CDK5R1'' gene. Function The protein encoded by this gene (p35) is a neuron-specific activator of cyclin-dependent kinase 5 (CDK5); the activation of CDK5 i ...

that serves as the activating subunit of CDK5, which is involved in the regulation of neuronal differentiation. CDK5RAP2 therefore has a role in neuronal differentiation. CDK5RAP2 is also necessary as a scaffolding protein in the centrosomal corona of ''

Dictyostelium ''Dictyostelium'' is a genus of single- and multi-celled eukaryotic, phagotrophic bacterivores. Though they are Protista and in no way fungal, they traditionally are known as "slime molds". They are present in most terrestrial ecosystems a ...

''.

Clinical significance

Human brain size variation

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...

study has demonstrated a link between common human variation in the CDK5RAP2 gene and brain structure. More specifically, associations were found between several

single nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...

s (SNPs) and brain cortical surface area and total brain volume. These associations were found exclusively in male subjects, and all SNPs were located either in the last 7

introns An intron is any Nucleic acid sequence, nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of ...

or downstream of the gene. The functional significance of these loci is not yet known. However, given their location close to

regulatory elements A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and vir ...

, it is possible that they are involved in

gene regulation Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wide ...

, which suggests that common variance in brain structure could be associated with differences in gene regulation rather than protein structure, consistent with findings in other complex human traits. CDK5RAP2 is a paralogue of

, which in mammals contains an

, a domain with human-specific duplications that have been implicated in human brain size evolution.

Autosomal recessive primary microcephaly

Mutations in CDK5RAP2 cause autosomal recessive primary

microcephaly Microcephaly (from Neo-Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it m ...

type 3.

Interactions

CDK5RAP2 has been shown to interact with

and

pericentrin Pericentrin (kendrin), also known as PCNT and pericentrin-B (PCNTB), is a protein which in humans is encoded by the ''PCNT'' gene on chromosome 21. This protein localizes to the centrosome and recruits proteins to the pericentriolar matrix (PCM ...

(PCTN).

History

The gene was discovered in 2000 and was first characterised in 2007.

References

External links

* {{UCSC gene info, CDK5RAP2 Centrosome