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Three views of a molecular model of human TMEM237-Cterm (Uniprot Q96Q45, residues 212-390, black cartoon), TMEM138 (Uniprot Q9NPI0, residues 1-162, rainbow cartoon, blue to red from N-term to C-term), and TMEM17 (Uniprot Q86X19, residues 37-198, white cartoon). Human TMEM138 residues His96, Ala126, Ala127 and Tyr130 - which when mutated cause Joubert syndrome 16 (JBTS16) - are in sticks representation.
Figure 1: three views of a molecular model of human TMEM237-Cterm (Uniprot Q96Q45, residues 212-390, black cartoon), TMEM138 (Uniprot Q9NPI0, residues 1-162, rainbow cartoon, blue to red from N-term to C-term), and TMEM17 (Uniprot Q86X19, residues 37-198, white cartoon). Human TMEM138 residues His96, Ala126, Ala127 and Tyr130 – which when mutated cause Joubert syndrome 16 (JBTS16) – are in sticks representation. A: the three proteins viewed from the side, in cilium membrane; extracellular side at the top, cytoplasmic side at the bottom; B: top view (from the extracellular side); C: bottom view (from the cytoplasm).

Transmembrane protein 138 is a protein that in humans is encoded by the TMEM138 gene.[5] Transmembrane protein 138 is an integral component of the Tectonic Complex (TC, aka Transition Zone Complex, TZC).[6] The TZC is a multi-protein complex [7] it forms the necklace of the cell’s primary cilium, a microscopic, hair-like structure protruding from the surface of a ciliate cell.[8] In all Eukaryotes, the cilium plays vital roles in sensory processing and signaling pathways.

Structure

In humans, the TMEM138 protein consists of 162 amino acids and has a predicted molecular weight of approximately 18.4 kilodaltons. It contains four transmembrane domains,[9] which span the lipid bilayer of cellular membranes.

Localization

TMEM138 has been observed in the ciliary transition zone (TZ), a critical region that connects the base of the cilium to the axoneme, another key structural component of the cilium. This localization has been demonstrated in cultured mouse cells[10] and in C. elegans.[11]

Function

Multiple components of the transition zone complex (TZC) assemble to form molecular barriers within the ciliary membrane, collectively known as the ciliary necklace. These structures restrict passive diffusion, preventing ciliary membrane proteins from exiting the cilium and non-ciliary membrane proteins from entering it.[8] As a result, membrane proteins must cross the ciliary necklace via active transport mechanisms. Like other TZC proteins, TMEM138 plays a crucial role in regulating protein localization and trafficking across the transition zone. For example, it appears to facilitate the proper ciliary transport and localization of rhodopsin, a key photoreceptor protein essential for vision.[10]== Genetic association ==

In humans, TMEM138 is encoded by the TMEM138 gene located on human chromosome 11. On this chromosome, the gene encoding TMEM138 is closely arranged in a head-to-tail configuration with another gene encoding a TZC component, TMEM216.[9] Both proteins belong to the TZC and are implicated in similar biological processes and share intergenic regulatory elements, suggesting a coordinated expression and function related to ciliogenesis, which is the formation and maintenance of cilia. In the elephant shark, the genes encoding TMEM138 and TMEM216 are found close to the one encoding TMEM80, another component of the TZC.[12]

Clinical relevance

Mutations in the TMEM138 gene have been linked to ciliopathies—a group of disorders arising from defects in ciliary structure and function.[9] One noted condition is Joubert syndrome (JBTS), a genetic disorder characterized by developmental delays and physical anomalies, including retinal dystrophy, seen as early-onset degeneration of photoreceptors.[13]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000149483 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024666 – 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. ^ “Entrez Gene: Transmembrane protein 138”. Retrieved 2012-01-30.
  6. ^ Zhang J, Humphreys IR, Pei J, Kim J, Choi C, Yuan R, et al. (October 2025). “Predicting protein-protein interactions in the human proteome”. Science. 390 (6771) eadt1630. Bibcode:2025Sci…390T1630Z. doi:10.1126/science.adt1630. PMID 40997207.
  7. ^ Gonçalves J, Pelletier L (April 2017). “The Ciliary Transition Zone: Finding the Pieces and Assembling the Gate”. Molecules and Cells. 40 (4): 243–253. doi:10.14348/molcells.2017.0054. PMC 5424270. PMID 28401750.
  8. ^ a b Gilula NB, Satir P (May 1972). “The ciliary necklace. A ciliary membrane specialization”. The Journal of Cell Biology. 53 (2): 494–509. doi:10.1083/jcb.53.2.494. PMC 2108734. PMID 4554367.
  9. ^ a b c Lee JH, Silhavy JL, Lee JE, Al-Gazali L, Thomas S, Davis EE, et al. (February 2012). “Evolutionarily assembled cis-regulatory module at a human ciliopathy locus”. Science. 335 (6071): 966–969. Bibcode:2012Sci…335..966L. doi:10.1126/science.1213506. PMC 3671610. PMID 22282472.
  10. ^ a b Guo D, Ru J, Xie L, Wu M, Su Y, Zhu S, et al. (April 2022). “Tmem138 is localized to the connecting cilium essential for rhodopsin localization and outer segment biogenesis”. Proceedings of the National Academy of Sciences of the United States of America. 119 (15) e2109934119. Bibcode:2022PNAS..11909934G. doi:10.1073/pnas.2109934119. PMC 9169668. PMID 35394880.
  11. ^ Li C, Jensen VL, Park K, Kennedy J, Garcia-Gonzalo FR, Romani M, et al. (March 2016). “MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone”. PLOS Biology. 14 (3) e1002416. doi:10.1371/journal.pbio.1002416. PMC 4794247. PMID 26982032.
  12. ^ Venkatesh B, Ravi V, Lee AP, Warren WC, Brenner S (January 2013). “Basal vertebrates clarify the evolutionary history of ciliopathy-associated genes Tmem138 and Tmem216”. Molecular Biology and Evolution. 30 (1): 62–65. doi:10.1093/molbev/mss215. PMC 3657383. PMID 22936720.
  13. ^ Shi Q, Zhu L, Zhang L, Guo Z, Hao Y, Wang Y, et al. (April 2025). “TMEM138: From Biological Functions to Diseases”. Physiological Research. 74 (2): 211–217. doi:10.33549/physiolres.935479. PMC 12148096. PMID 40432436.

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