Muskelin

Protein-coding gene in the species Homo sapiens

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
| View/Edit Human| View/Edit Mouse

|

Muskelin is a protein that in humans is encoded by the MKLN1 gene.[5][6]

## Gene

[edit]

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]

## Protein

[edit]

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]

## CTLH complex

[edit]

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]

## Species distribution

[edit]

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]

## Clinical significance

[edit]

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]

## References

[edit]

1. ^ a b c GRCh38: Ensembl release 89: ENSG00000128585 – Ensembl, May 2017
2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025609 – Ensembl, May 2017
3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. ^ Adams JC, Zhang L (May 2000). "cDNA cloning of human muskelin and localisation of the muskelin (MKLN1) gene to human chromosome 7q32 and mouse chromosome 6 B1/B2 by physical mapping and FISH". Cytogenetics and Cell Genetics. 87 (1–2): 19–21\. doi:10.1159/000015385. PMID 10640805. S2CID 7919425.1–2&rft.pages=19-21&rft.date=2000-05&rft_id=https://api.semanticscholar.org/CorpusID:7919425#id-name=S2CID&rft_id=info:pmid/10640805&rft_id=info:doi/10.1159/000015385&rft.aulast=Adams&rft.aufirst=JC&rft.au=Zhang,+L&rfr_id=info:sid/en.wikipedia.org:Muskelin" class="Z3988">
6. ^ "Entrez Gene: MKLN1 muskelin 1, intracellular mediator containing kelch motifs".
7. ^ "UniProt". UniProt. Retrieved 2025-04-07.
8. ^ "Gene: MKLN1 (ENSG00000128585) - Summary - Homo_sapiens - Ensembl genome browser 109". feb2023.archive.ensembl.org. Retrieved 2025-04-07.
9. ^ a b "Gene : MKLN1 - ENSG00000128585 - Homo sapiens (human)". www.bgee.org. Retrieved 2025-04-07.
10. ^ a b c d e Maitland ME, Lajoie GA, Shaw GS, Schild-Poulter C (May 2022). "Structural and Functional Insights into GID/CTLH E3 Ligase Complexes". International Journal of Molecular Sciences. 23 (11): 5863. doi:10.3390/ijms23115863. PMC 9180843. PMID 35682545.
11. ^ Damgaard RB (February 2021). "The ubiquitin system: from cell signalling to disease biology and new therapeutic opportunities". Cell Death and Differentiation. 28 (2): 423–426\. doi:10.1038/s41418-020-00703-w. PMC 7862391. PMID 33446876.
12. ^ a b c Maitland ME, Onea G, Owens DD, Gonga-Cavé BC, Wang X, Arrowsmith CH, et al. (December 2024). "Interplay between β-propeller subunits WDR26 and muskelin regulates the CTLH E3 ligase supramolecular complex". Communications Biology. 7 (1): 1668. doi:10.1038/s42003-024-07371-3. PMC 11659599. PMID 39702571.
13. ^ Maitland ME, Onea G, Chiasson CA, Wang X, Ma J, Moor SE, et al. (July 2019). "The mammalian CTLH complex is an E3 ubiquitin ligase that targets its subunit muskelin for degradation". Scientific Reports. 9 (1): 9864. Bibcode:2019NatSR...9.9864M. doi:10.1038/s41598-019-46279-5. PMC 6614414. PMID 31285494.
14. ^ Prag S, De Arcangelis A, Georges-Labouesse E, Adams JC (2007-01-01). "Regulation of post-translational modifications of muskelin by protein kinase C". The International Journal of Biochemistry & Cell Biology. 39 (2): 366–378\. doi:10.1016/j.biocel.2006.09.003. PMID 17049906.
15. ^ "Search results < Expression Atlas < EMBL-EBI". www.ebi.ac.uk. Retrieved 2025-04-08.
16. ^ Gross A, Müller J, Chrustowicz J, Strasser A, Gottemukkala KV, Sherpa D, et al. (May 2024). "Skraban-Deardorff intellectual disability syndrome-associated mutations in WDR26 impair CTLH E3 complex assembly". FEBS Letters. 598 (9): 978–994\. doi:10.1002/1873-3468.14866. PMC 7616460. PMID 38575527.
17. ^ Nassan M, Li Q, Croarkin PE, Chen W, Colby CL, Veldic M, et al. (January 2017). "A genome wide association study suggests the association of muskelin with early onset bipolar disorder: Implications for a GABAergic epileptogenic neurogenesis model". Journal of Affective Disorders. 208: 120–129\. doi:10.1016/j.jad.2016.09.049. PMID 27769005.

## Further reading

[edit]

* Adams JC, Seed B, Lawler J (September 1998). "Muskelin, a novel intracellular mediator of cell adhesive and cytoskeletal responses to thrombospondin-1". The EMBO Journal. 17 (17): 4964–4974\. doi:10.1093/emboj/17.17.4964. PMC 1170825. PMID 9724633.
* Hasegawa H, Katoh H, Fujita H, Mori K, Negishi M (September 2000). "Receptor isoform-specific interaction of prostaglandin EP3 receptor with muskelin". Biochemical and Biophysical Research Communications. 276 (1): 350–354\. doi:10.1006/bbrc.2000.3467. PMID 11006128.
* Umeda M, Nishitani H, Nishimoto T (January 2003). "A novel nuclear protein, Twa1, and Muskelin comprise a complex with RanBPM". Gene. 303: 47–54\. doi:10.1016/S0378-1119(02)01153-8. PMID 12559565.
* Prag S, Collett GD, Adams JC (July 2004). "Molecular analysis of muskelin identifies a conserved discoidin-like domain that contributes to protein self-association". The Biochemical Journal. 381 (Pt 2): 547–559\. doi:10.1042/BJ20040253. PMC 1133863. PMID 15084145.
* Kobayashi N, Yang J, Ueda A, Suzuki T, Tomaru K, Takeno M, et al. (July 2007). "RanBPM, Muskelin, p48EMLP, p44CTLH, and the armadillo-repeat proteins ARMC8alpha and ARMC8beta are components of the CTLH complex". Gene. 396 (2): 236–247\. doi:10.1016/j.gene.2007.02.032. PMID 17467196.

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