The human transmembrane (TM) and tetratricopeptide repeat (TPR) protein family (TMTC) consists of four main members: TMTC1, TMTC2, TMTC3, and TMTC4. The specific functions of these proteins within cells have long remained unknown, but recent studies have unveiled their potential roles in various diseases.
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Structural Characteristics of the TMTC Protein Family
The TMTC protein family shares common sequence structures, including an N-terminal fragment with transmembrane regions and intermittent loops, and multiple C-terminal extensions arranged in sequences of 10 TPR repeats. The four members of the TMTC family are TMTC1 (subtype X3, germline XP_016875493, 875 amino acids), TMTC2 (Q8N394, 830 amino acids), TMTC3 (Q6ZXV5, 915 amino acids), and TMTC4 (Q5T4D3, 741 amino acids).
Fig. 1 Structure models of TMTC1/2/3/4 with ligands (Eisenhaber B., et al. 2021).
While the structure of TMTC proteins shows consistency in some aspects, the number and positions of their specific transmembrane regions vary among members. For instance, TMTC1 and TMTC2 are associated with intracellular calcium homeostasis, whereas TMTC3 and TMTC4 are more involved in the endoplasmic reticulum (ER) stress response and the unfolded protein response. Although TMTC proteins have different localizations and functions in the ER, they collectively participate in a new O-mannosylation pathway, selectively targeting cadherin-like molecules.
Disease Associations of TMTC Proteins
TMTC1
TMTC1 has been implicated in schizophrenia by multiple studies. Genome-wide association studies (GWAS) have highlighted a significant association between TMTC1 and this neuropsychiatric disorder. Additionally, TMTC1 is differentially expressed in inflammatory bowel disease-associated arthritis, further supporting its role in immune-related diseases. Recent research also found that circular RNA circTMTC1 inhibits the differentiation of chicken skeletal muscle satellite cells, suggesting its potential role in muscle development and regeneration.
TMTC2
TMTC2 is one of the most extensively studied members of the TMTC family. GWAS and family studies have linked TMTC2 to non-syndromic sensorineural hearing loss (SNHL). Furthermore, TMTC2 is associated with obesity, increased left ventricular mass, eczema, asthma, and other immune diseases. These findings indicate that TMTC2 plays a crucial role in various physiological and pathological processes.
Although the initial GWAS linked TMTC2 to primary open-angle glaucoma, subsequent studies failed to confirm this association in different racial cohorts, including African-Caribbean, Chinese, Japanese, Korean, Saudi Arabian, and South Indian populations. However, new evidence in mixed-race cohorts re-emphasizes this connection, particularly affecting the optic disc region.
TMTC3
Mutations in TMTC3 have been shown to cause cobblestone lissencephaly and periventricular nodular heterotopia with intellectual disability and epilepsy. Additionally, TMTC3 plays a potential role in the ER stress response, with its mutations potentially leading to exacerbated ER stress and apoptosis. Mouse model studies indicate that the knockout of TMTC3 delays gastrulation, further supporting its critical role in developmental processes.
TMTC4
In mouse studies, the gene inactivation of TMTC4 leads to rapid postnatal death of cochlear hair cells, resulting in hearing loss. TMTC4 also plays a role in bone density regulation, as revealed by transcriptome-wide association studies. Further research indicates that TMTC4's involvement in the unfolded protein response may relate to its role in cellular stress responses.
Molecular and Cellular Functions of TMTC Proteins
Recent studies have revealed the specific functions of TMTC proteins within cells, particularly in the O-mannosylation pathway. By knocking out all four TMTC proteins in HEK293 cells, researchers found that this elimination disrupts the O-mannosylation of various cadherins and protocadherins. Therefore, TMTC proteins are recognized as members of a novel O-mannosylation pathway that selectively targets cadherin-like molecules.
Mass spectrometry analysis shows that selective knockout of TMTC1 or TMTC3 results in a larger set of O-mannosylated glycopeptides, indicating the specific roles of different TMTC proteins in glycosylation lineages. In the context of HEK293 cells with a combined knockout of all four TMTC proteins, TMTC3 complementation rescued the O-mannosylation of E-cadherin and enhanced cell adhesion.
Mechanistic Studies of TMTC Proteins in Diseases
The roles of TMTC proteins in various diseases have garnered widespread attention, especially their potential mechanisms in neurological, immune, and metabolic disorders.
Neurological Disorders
The roles of TMTC1 and TMTC2 in neurological disorders have been widely studied. The association of TMTC1 with schizophrenia suggests its critical role in neurodevelopment or neurotransmission. TMTC2's association with non-syndromic sensorineural hearing loss further supports its importance in the auditory system. Additionally, the interaction between TMTC2 and certain miRNAs suggests its potential role in Parkinson's disease, possibly through the regulation of neuronal survival and function.
Immune and Inflammatory Diseases
The association of TMTC2 with immune diseases such as eczema, asthma, and the "atopic march" indicates its crucial role in immune regulation. The differential expression of TMTC1 in inflammatory bowel disease-associated arthritis also supports its potential function in inflammatory responses. These findings suggest that TMTC proteins may influence the development and progression of immune and inflammatory diseases by regulating immune cell functions and the expression of inflammatory factors.
Metabolic Diseases
GWAS showing the association of TMTC2 with obesity and increased left ventricular mass suggests its role in metabolic regulation and cardiovascular health. TMTC4's role in bone density regulation also indicates its potential function in bone metabolism. These findings suggest that TMTC proteins may regulate the development and progression of metabolic diseases by affecting metabolic pathways and tissue-specific functions.
Conclusion
The TMTC protein family plays significant roles in cellular functions and disease mechanisms. Although their specific molecular mechanisms require further investigation, existing evidence indicates that TMTC proteins have diverse and pleiotropic effects in neurological, immune, metabolic, and developmental processes. Future research should continue to explore the specific functions and mechanisms of TMTC proteins to reveal their potential therapeutic targets and applications in disease treatment. By gaining a deeper understanding of TMTC proteins' functions, we can better comprehend their critical roles in health and disease, providing new insights for the diagnosis and treatment of related conditions.
References
- Eisenhaber B., et al. Conserved sequence motifs in human TMTC1, TMTC2, TMTC3, and TMTC4, new O-mannosyltransferases from the GT-C/PMT clan, are rationalized as ligand binding sites. Biology Direct. 2021, 16: 1-8.
- Larsen I.S., et al. Multiple distinct O-Mannosylation pathways in eukaryotes. Current Opinion in Structural Biology. 2019, 56: 171-8.
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