Muskelin

MKLN1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4PQQ
Identifiers
Aliases	MKLN1, TWA2, muskelin 1
External IDs	OMIM: 605623; MGI: 1351638; HomoloGene: 8305; GeneCards: MKLN1; OMA:MKLN1 - orthologs
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7q32.3 Start 131,110,096 bp[1] End 131,496,632 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6|6 A3.3 Start 31,375,670 bp[2] End 31,493,746 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Achilles tendon jejunal mucosa buccal mucosa cell nipple lower lobe of lung epithelium of colon testicle corpus callosum secondary oocyte tail of epididymis Top expressed in spermatocyte yolk sac right kidney muscle of thigh spermatid ventricular zone granulocyte tail of embryo neural layer of retina genital tubercle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function identical protein binding protein binding protein homodimerization activity Cellular component cytoplasm ruffle cytosol cell projection cell cortex ubiquitin ligase complex nucleoplasm nucleus cell junction synapse Biological process actin cytoskeleton reorganization cell-matrix adhesion signal transduction regulation of cell shape regulation of receptor internalization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4289 27418 Ensembl ENSG00000128585 ENSMUSG00000025609 UniProt Q9UL63 O89050 RefSeq (mRNA) NM_001145354 NM_013255 NM_001321316 NM_013791 RefSeq (protein) NP_001138826 NP_001308245 NP_037387 NP_038819 Location (UCSC) Chr 7: 131.11 – 131.5 Mb Chr 6: 31.38 – 31.49 Mb PubMed search [3] [4]
Wikidata
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Muskelin is a protein that in humans is encoded by the MKLN1 gene.^[5][6]

In humans, the MKLN1 gene is located on the long arm of chromosome 7 (7q32.3).^[7] It produces 12 splice variant transcripts, 6 of which are translated into a protein product.^[8] It is widely expressed across human tissues.^[9]

At its N-terminus, muskelin has a disicoidin domain. This is followed by the alpha helical domains Lis1 Homology (LisH) and C-terminal to LisH (CTLH). After these lies the kelch repeat β-propellor domain, followed at the C-terminus by the CRA domain. Muskelin acts as a scaffold in the C-terminal to LisH (CTLH) E3 ligase complex. It is one of two proteins, along with WDR26, that can facilitate the formation of a massive supramolecular structure (600 kDa).^[10]

Muskelin is a component of the CTLH complex, which assembles into distinct supramolecular structures depending on whether WDR26 or muskelin acts as the β-propeller subunit. The CTLH complex is a recently characterized RING E3 ubiquitin ligase. As an E3 ligase, it catalyzes the final step of the ubiquitination cascade by mediating the interaction between a ubiquitin-conjugating enzyme (E2) and the substrate protein targeted for ubiquitination.^[11] The CTLH complex primarily functions within the ubiquitin-proteasome system, tagging proteins for degradation by the 26S proteasome.

The complex consists of several core components. Its structural scaffold is formed by RanBPM, GID8, and ARMC8. The RING heterodimer, composed of RMND5A and MAEA, is responsible for the complex’s E3 ligase activity by directly interacting with the E2 enzyme. GID4 functions as the primary substrate receptor, recognizing and recruiting proteins targeted for ubiquitination.^[10]

WDR26 and muskelin act in a mutually exclusive manner to promote the assembly of a higher-order CTLH structure, which includes four scaffold units, two RING heterodimers, and two GID4 receptors. WDR26 achieves this through binding as a pair of homodimers, while muskelin binds as a pair of homotetramers, each inserting between scaffold units to stabilize the supramolecular structure.^[10]

These WDR26- and muskelin-containing complexes are functionally distinct due to differences in their substrate-binding interfaces. This structural variation enables them to recruit different sets of substrates. In muskelin knockout cells, expression levels of 39 proteins are altered, 16 of which are also affected by WDR26 knockout, indicating 23 proteins are specifically regulated by the muskelin-containing CTLH complex.^[12]

The muskelin-containing complex also regulates its own activity via a negative feedback mechanism. It has been shown to ubiquitinate and promote the degradation of muskelin itself, a process not observed with WDR26 or other subunits.^[13][12] This autoregulation substitutes for alternative substrate receptors, helping maintain appropriate substrate levels.^[12]

Through its two distinct configurations, the CTLH complex participates in a wide range of cellular processes, including metabolism, cell proliferation and survival, the maternal to zygotic transition, cell migration and adhesion, immune responses, autophagy, and erythropoiesis.^[10] Accordingly, muskelin is broadly expressed across diverse tissues and cell types.^[14][15][9]

The CTLH complex was first discovered in Saccharomyces cerevisiae (Brewer's yeast), however here it lacks a muskelin homologue. Similarly, it also lacks a muskelin homologue in plants and nematodes, however it does exist in higher order animals such as mammals, fish and amphibians.^[10]

The CTLH complex is mostly implicated in neurological conditions. The most well understood of these is Skraban–Deardorff syndrome, a neurodevelopmental disorder caused by a multitude of WDR26 mutations impairing its ability to form the supramolecular structure.^[16] A particular muskelin SNP has been linked withn early-onset bipolar disorder via a genome-wide association study, however the biological mechanism for this is unclear.^[17]

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