Affinage

DRC5

Dynein regulatory complex subunit 5 · UniProt Q5JU00

Length
501 aa
Mass
55.6 kDa
Annotated
2026-06-09
16 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TCTE1/DRC5 is an evolutionarily conserved axonemal protein that functions as a structural component of the nexin-dynein regulatory complex (N-DRC) in the sperm flagellum, where it is required for flagellar motility and male fertility (PMID:28630322). TCTE1 is required for assembly of the N-DRC and its transport to the flagellum: in its absence the protein is retained only in residual amounts in the sperm head nucleus and other N-DRC subunits (DRC7, FBXL13/DRC6, EPS8L1/DRC3) fail to reach the flagellum (PMID:38650655). Within the complex, TCTE1 physically interacts with FBXL13 (DRC6) and DRC7, with DRC7 being required to incorporate TCTE1 and other components into the flagellum (PMID:31961863), and it also associates with ANKEF1 in a calcium-independent manner, contributing to N-DRC-mediated mechanical buffering between adjacent doublet microtubules (PMID:41460250). Loss of TCTE1 produces aberrant sperm motility with reduced sperm ATP levels despite structurally normal axonemes, linking the protein to the energy supply required for dynein motor function (PMID:28630322, PMID:38650655). Bi-allelic loss-of-function variants in human TCTE1 cause asthenospermia and male infertility, establishing a conserved requirement for flagellar motility (PMID:35388187).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2017 High

    Established TCTE1/DRC5 as a flagellar N-DRC component whose loss causes male sterility, answering whether the protein has a functional role in sperm motility and energy metabolism.

    Evidence Tcte1-null mouse knockout with flagellar immunofluorescence, ATP measurement, and axoneme electron microscopy

    PMID:28630322

    Open questions at the time
    • Mechanism linking TCTE1 loss to reduced ATP not defined
    • Direct binding partners within the N-DRC not yet identified
    • Whether axoneme is biochemically as well as structurally intact unresolved
  2. 2020 Medium

    Defined TCTE1's molecular partners and assembly hierarchy, showing it interacts with FBXL13 and DRC7 and that DRC7 is required to incorporate TCTE1 into the flagellum.

    Evidence Drc7 and Fbxl13 knockout mice with immunofluorescence and Western blot for N-DRC component localization

    PMID:31961863

    Open questions at the time
    • TCTE1-DRC6/DRC7 interactions not independently replicated
    • Direct vs indirect nature of interactions not resolved
    • Stoichiometry within N-DRC unknown
  3. 2022 Medium

    Extended the requirement for TCTE1 to humans, showing bi-allelic loss-of-function variants cause asthenospermia and infertility.

    Evidence Whole-exome sequencing of an infertile patient with protein degradation assay and clinical semen analysis

    PMID:35388187

    Open questions at the time
    • Single human case limits genotype-phenotype generalization
    • No structural analysis of patient sperm axonemes
    • Mechanism of mutant protein degradation not characterized
  4. 2024 High

    Demonstrated that TCTE1 is required for N-DRC assembly and transport to the flagellum, with broader effects on sperm morphology, ATP, and gene expression.

    Evidence CRISPR/Cas9 Tcte1 knockout mice with N-DRC protein localization, ATP luminescence assay, semen analysis, and RNA-seq

    PMID:38650655

    Open questions at the time
    • Why residual TCTE1 localizes to the sperm head nucleus unexplained
    • Causal link between transcriptional changes and phenotype not established
    • Order of N-DRC subunit recruitment not fully mapped
  5. 2025 Medium

    Identified ANKEF1 as a calcium-independent TCTE1 partner and connected the complex to mechanical buffering of doublet microtubules.

    Evidence Co-immunoprecipitation of ANKEF1 with DRC5/TCTE1 and DRC4/GAS8, Ankef1 knockout mice, and cryo-electron tomography

    PMID:41460250

    Open questions at the time
    • Co-IP not reciprocally validated for direct binding
    • Functional consequence of TCTE1-ANKEF1 interaction for motility untested
    • Whether mechanical buffering is mediated by TCTE1 itself unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TCTE1 mechanistically couples N-DRC integrity to sperm ATP levels and dynein motor regulation remains unresolved.
  • No structural model of TCTE1 within the assembled N-DRC
  • Mechanism connecting TCTE1 loss to reduced ATP undefined
  • Direct biochemical demonstration of TCTE1 binding interfaces lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005856 cytoskeleton 2
Pathway
R-HSA-1474165 Reproduction 3
Partners
ANKEF1DRC7FBXL13
Complex memberships
nexin-dynein regulatory complex (N-DRC)

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 TCTE1 (DRC5) is a conserved component of the nexin-dynein regulatory complex (N-DRC) of the axoneme, localized to the flagellum of mouse spermatozoa. Knockout of Tcte1 causes male sterility with aberrant sperm motility despite structurally normal axonemes, and Tcte1-null sperm show a significant decrease in ATP levels, linking TCTE1 to energy metabolism required for dynein motor function. Mouse knockout (Tcte1-null), immunofluorescence localization, ATP measurement, transmission electron microscopy, Northern/Western blot Proceedings of the National Academy of Sciences of the United States of America High 28630322
2020 TCTE1 (DRC5) interacts with FBXL13 (DRC6) and DRC7 within the N-DRC complex in the mammalian sperm flagellum. DRC7 (but not FBXL13) is required for correct assembly of the N-DRC and for incorporating other N-DRC components, including TCTE1, into the flagellum. Mouse knockout of Drc7 and Fbxl13, immunofluorescence, electron microscopy of axoneme structure, Western blot for N-DRC component localization PLoS genetics Medium 31961863
2022 Bi-allelic loss-of-function frameshift variants in human TCTE1/DRC5 cause asthenospermia and male infertility, with structurally normal but low-motility sperm, confirming the conserved requirement of TCTE1 for flagellar motility in humans. Whole-exome sequencing of infertile patient, protein degradation assay (Western blot showing rapid degradation of mutant TCTE1), clinical semen analysis, IVF rescue experiment European journal of human genetics : EJHG Medium 35388187
2024 In Tcte1 knockout mice, Tcte1 protein is present only in residual amounts in the sperm head nucleus and is not transported to the sperm flagella; other N-DRC components (DRC7, FBXL13/DRC6, EPS8L1/DRC3) are also absent from the flagella, indicating TCTE1 is required for N-DRC complex assembly and transport to the flagellum. Knockout causes oligoasthenoteratozoospermia with 2.4-fold reduced sperm ATP and disturbed tail:midpiece ratios. Haploinsufficiency causes oligozoospermia. RNA-seq revealed 21 differentially expressed genes related to mitochondrial ATP processing, apoptosis, or spermatogenesis. CRISPR/Cas9 Tcte1 knockout mice, immunofluorescence localization of N-DRC proteins in sperm, ATP luminescence assay, semen analysis, RNAseq, protein prediction modeling of human variants Human reproduction open High 38650655
2025 DRC5/TCTE1 physically interacts with ANKEF1 (ANKRD5) within the N-DRC of the sperm axoneme. This interaction occurs independently of calcium regulation. ANKEF1 deficiency does not alter ATP levels but causes increased structural heterogeneity of doublet microtubules, suggesting TCTE1 participates in N-DRC-mediated mechanical buffering between adjacent doublet microtubules. Co-immunoprecipitation of ANKEF1 with DRC5/TCTE1 and DRC4/GAS8, Ankef1 knockout mice, cryo-electron tomography of sperm axoneme, ATP/ROS/mitochondrial membrane potential measurements eLife Medium 41460250
1998 The N-terminal domain of TCTE1 shows species-specific sequence divergence correlated with heterospecific sperm-egg binding ability, suggesting the TCTE1 sperm polypeptide contributes to species-specific sperm function; the protein is expressed in early stages of spermatogenesis and is absolutely required for fertilization in mouse. Comparative amino acid sequence analysis of TCTE1 N-terminal regions across rodent species; heterospecific sperm-egg binding assay Journal of andrology Low 9570741

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 The gene for autosomal dominant spinocerebellar ataxia (SCA1) maps telomeric to the HLA complex and is closely linked to the D6S89 locus in three large kindreds. American journal of human genetics 126 2063871
1995 Genetic mapping of cleidocranial dysplasia and evidence of a microdeletion in one family. Human molecular genetics 98 7711736
1993 Linkage analysis of idiopathic generalized epilepsy (IGE) and marker loci on chromosome 6p in families of patients with juvenile myoclonic epilepsy: no evidence for an epilepsy locus in the HLA region. American journal of human genetics 91 8352275
2017 TCTE1 is a conserved component of the dynein regulatory complex and is required for motility and metabolism in mouse spermatozoa. Proceedings of the National Academy of Sciences of the United States of America 85 28630322
2020 Nexin-Dynein regulatory complex component DRC7 but not FBXL13 is required for sperm flagellum formation and male fertility in mice. PLoS genetics 40 31961863
1996 Cloning, expression, and mapping of TCTEL1, a putative human homologue of murine Tcte1, to 6q. Cytogenetics and cell genetics 29 8646886
1991 Linkage mapping and fluorescence in situ hybridization of TCTE1 on human chromosome 6p: analysis of dinucleotide polymorphisms on native gels. Genomics 29 1916824
2015 Comparative analysis of testis transcriptomes from triploid and fertile diploid cyprinid fish. Biology of reproduction 28 25761592
1998 Physical map of human 6p21.2-6p21.3: region flanking the centromeric end of the major histocompatibility complex. Genome research 28 9647638
2022 Bi-allelic variants in human TCTE1/DRC5 cause asthenospermia and male infertility. European journal of human genetics : EJHG 19 35388187
1994 Linkage analysis of a candidate locus (HLA) in autosomal dominant sacral defect with anterior meningocele. American journal of medical genetics 10 7977450
2016 Variation in PTCHD2, CRISP3, NAP1L4, FSCB, and AP3B2 associated with spherical equivalent. Molecular vision 9 27440996
1998 Sequence divergence within the sperm-specific polypeptide TCTE1 is correlated with species-specific differences in sperm binding to zona-intact eggs. Journal of andrology 8 9570741
2024 Genetic susceptibility of diffuse large B-cell lymphoma: a meta genome-wide association study in Asian population. Leukemia 4 39707004
2025 ANKEF1 is a key axonemal component essential for murine sperm motility and male fertility. eLife 1 41460250
2024 Effects of Tcte1 knockout on energy chain transportation and spermatogenesis: implications for male infertility. Human reproduction open 1 38650655

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