DNAJC19 (TIM14 / TIMM14) research notes

Identity

• UniProt Q96DA6, TIM14_HUMAN, "Mitochondrial import inner membrane translocase subunit TIM14"; DnaJ homolog subfamily C member 19. 116 aa.
• HGNC:30528. Chromosome 3. Belongs to the TIM14 family.
• Topology: short intermembrane-space N-terminus (2-3), single transmembrane helix (4-24), then matrix-side J-domain (62-116). So a single-pass inner-membrane protein with its catalytic J-domain projecting into the matrix.

Core function

• J-domain co-chaperone of the mitochondrial presequence translocase-associated import motor (PAM), the matrix-side motor of the TIM23 complex.
• Stimulates the ATPase activity of mitochondrial HSP70 (mortalin/HSPA9) to drive ATP-dependent import of presequence-bearing precursor proteins across the inner membrane into the matrix.
• PMID:19564938
• Human DNAJC19 directly stimulates human mtHSP70 (Mortalin) ATPase activity; this is antagonized by Magmas/PAM16 PMID:20053669.

Partner / complex

• Forms a stable heterodimeric subcomplex with Magmas (PAM16/TIMM16) through their related J/J-like domains; this is the regulatory module of the import motor. Demonstrated in human mitochondria by reciprocal coIP.
• PMID:20053669
• PMID:20053669
• Part of the human TIM23 translocon: co-IP with Tim17 pulls down hTim44, hTim23, DnaJC19, Magmas PMID:20053669.
• Human Tim14/Pam18 (DNAJC19) and human Tim16/Pam16 form hetero-oligomers and bind yeast mtHsp70 PMID:19564938.
• UniProt SUBUNIT: interacts with PHB2 (associates DNAJC19 with prohibitin complex) and with TIMM16/PAM16; may be component of PAM complex (mtHSP70, GRPEL1/2, TIMM44, TIMM16, TIMM14). (By similarity.)

Localization

• Mitochondrion inner membrane, single-pass, matrix side [UniProt SUBCELLULAR LOCATION]. Confirmed in human heart mito proteome PMID:12592411 and human mito proteome PMID:34800366.

Second function (cardiolipin)

• UniProt FUNCTION (by similarity): "forms a complex with prohibitins to regulate cardiolipin remodeling." Underlies the 3-methylglutaconic aciduria / DCMA phenotype (a cardiolipin/Barth-like syndrome). This is ISS/by-similarity, kept as non-core but plausible.

Disease

• DCMA syndrome = dilated cardiomyopathy with ataxia = 3-methylglutaconic aciduria type 5 (MGCA5), autosomal recessive PMID:16055927. Also testicular dysgenesis (genitalia development), optic features. The IMP annotations to "genitalia development" and "visual perception" derive from the human disease phenotype description.

Annotation review reasoning

• Core MF: GO:0001671 ATPase activator activity (stimulates mtHSP70) - ACCEPT, directly demonstrated for human protein.
• Core BP: GO:0030150 protein import into mitochondrial matrix - ACCEPT.
• Core CC: PAM complex (GO:0001405) and mitochondrial inner membrane / matrix side - ACCEPT.
• TIM23 translocase complex (GO:0005744) part_of - ACCEPT, human translocon coIP.
• Cardiolipin regulation (GO:1900208) ISS/IEA - KEEP_AS_NON_CORE (by similarity, disease-relevant but secondary).
• protein binding GO:0005515 IPI with Q9Y3D7 (=PAM16/Magmas) - KEEP_AS_NON_CORE (real interaction, uninformative term; informative is the J-domain/ATPase module).
• protein-containing complex GO:0032991 IDA - KEEP_AS_NON_CORE (generic, real but redundant with PAM/TIM23 complex).
• mitochondrion GO:0005739 IDA/HTP - ACCEPT (less specific than inner membrane but correct).
• membrane GO:0016020 NAS - KEEP_AS_NON_CORE (generic).
• intracellular protein transport GO:0006886 NAS - KEEP_AS_NON_CORE (generic parent of import into matrix).
• Note: genitalia development / visual perception IMP terms are in the DR/UniProt GO set but NOT in the GOA tsv stub, so not reviewed here.