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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''CDK5RAP2''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. It has necessary roles in the

formation Formation may refer to: Linguistics * Back-formation, the process of creating a new lexeme by removing or affixes * Word formation, the creation of a new word by adding affixes Mathematics and science * Cave formation or speleothem, a secondar ...

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 prog ...

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'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...

'' protein centrosomin (cnn) and

paralogous Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...

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 formation of microtubules from the centrosome. Its nam ...

, 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 evol ...

, a domain implicated in human brain size evolution.

Function

CDK5RAP2 is necessary for the proper

, anchoring and orientation of

from the

. It binds with the

γ-tubulin Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoske ...

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 is ...

that serves as the activating subunit of

CDK5 Cyclin-dependent kinase 5 is a protein, and more specifically an enzyme, that is encoded by the Cdk5 gene. It was discovered 15 years ago, and it is saliently expressed in post-mitotic central nervous system neurons (CNS). The molecule belongs ...

, 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 biology, scaffold proteins are crucial regulators of many key signalling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signalling pathway, tethering them in ...

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 as ...

''.

Clinical significance

Human brain size variation

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

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, 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 a sufficiently larg ...

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 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 the cistron .e., gene ...

downstream Downstream may refer to: * Downstream (bioprocess) * Downstream (manufacturing) * Downstream (networking) * Downstream (software development) * Downstream (petroleum industry) * Upstream and downstream (DNA), determining relative positions on DNA ...

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 vi ...

, 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 wi ...

, 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 Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a s ...

, 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 New 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 ...

type 3.

Interactions

CDK5RAP2 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

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