DNAJC19

DnaJ (Hsp40) homolog, subfamily C, member 19
Identifiers
Symbols	DNAJC19 ; PAM18; TIM14; TIMM14
External IDs	OMIM: 608977 HomoloGene: 87176 GeneCards: DNAJC19 Gene
Gene ontology Molecular function • ATPase activator activity • protein binding • protein transporter activity Cellular component • presequence translocase-associated import motor • mitochondrion • mitochondrial inner membrane • integral component of membrane • protein complex Biological process • protein folding • protein targeting to mitochondrion • visual perception • protein import into mitochondrial matrix • positive regulation of ATPase activity • cellular protein metabolic process • genitalia development Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	131118	67713
Ensembl	ENSG00000205981	ENSMUSG00000027679
UniProt	Q96DA6	Q9CQV7
RefSeq (mRNA)	NM_001190233	NM_001026211
RefSeq (protein)	NP_001177162	NP_001021382
Location (UCSC)	Chr 3: 180.98 – 180.99 Mb	Chr 3: 34.06 – 34.08 Mb
PubMed search

Mitochondrial import inner membrane translocase subunit TIM14 is an enzyme that in humans is encoded by the DNAJC19 gene on chromosome 3.^[1][2] TIM14 belongs to the DnaJ family, which has been involved in Hsp40/Hsp70 chaperone systems.^[3][4] As a mitochondrial chaperone, TIM14 functions as part of the TIM23 complex import motor to facilitate the import of nuclear-encoded proteins into the mitochondria.^[3] TIM14 also complexes with prohibitin complexes to regulate mitochondrial morphogenesis, and has been implicated in dilated cardiomyopathy with ataxia.^[5]

Structure

The protein encoded by the DNAJC19 gene possesses an unusual structure compared to the rest of the DNAJ protein family. Notably, the DNAJ domain of TIM14 is located at the C-terminal rather than the N-terminal, and the transmembrane domain confers membrane-bound localization for TIM14 while other DNAJ proteins are cytosolic. TIM14 orthologs in other species, such as the yeast Tim14 and Mdj2p proteins, confirm localization to the mitochondrial inner membrane.^[6]

Function

TIM14 is required for the ATP-dependent import of mitochondrial pre-proteins into the mitochondrial matrix.The J-domain of TIM14 stimulates mtHsp70 ATPase activity to power this transport.^[3]

Additionally, TIM14 helps regulate mitochondrial morphology by complexing with prohibitins to perform disphosphoglycerolipid cardiolipin (CL) remodeling. CL is a key phospholipid in mitochondrial membranes that modulates the fusion and fission of mitochondrial membranes, as well as mitophagy and apoptosis.^[5]

Clinical significance

Defects in DNAJC19 have been observed primarily in cases of dilated cardiomyopathy with ataxia (DCMA), though it has also been associated with growth failure, microcytic anemia, and male genital anomalies. DNAJC19 was first implicated in DCMA in a study on the consanguineous Hutterite population, which has since been confirmed in other European populations.^[4][7] In the clinic, DNAJC19 mutations can be detected by screening for elevated levels of 3-methylglutaconic acid, mitochondrial distress, dilated cardiomyopathy, prolongation of the QT interval in the electrocardiogram, and cerebellar ataxia.^[7][8]

Interactions

TIM14 interacts with:

• TIMM44,^[3]
• mtHsp70,^[3]
• TIMM16/PAM16,^[9] and
• PHB2.^[5]

References

1. Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, et al. (Dec 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
2. "Entrez Gene: DNAJC19 DnaJ (Hsp40) homolog, subfamily C, member 19".
3. Mokranjac D, Sichting M, Neupert W, Hell K (Oct 2003). "Tim14, a novel key component of the import motor of the TIM23 protein translocase of mitochondria". The EMBO Journal 22 (19): 4945–56. doi:10.1093/emboj/cdg485. PMC 204468. PMID 14517234.
4. Davey KM, Parboosingh JS, McLeod DR, Chan A, Casey R, Ferreira P, Snyder FF, Bridge PJ, Bernier FP (May 2006). "Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition". Journal of Medical Genetics 43 (5): 385–93. doi:10.1136/jmg.2005.036657. PMC 2564511. PMID 16055927.
5. Richter-Dennerlein R, Korwitz A, Haag M, Tatsuta T, Dargazanli S, Baker M, Decker T, Lamkemeyer T, Rugarli EI, Langer T (Jul 2014). "DNAJC19, a mitochondrial cochaperone associated with cardiomyopathy, forms a complex with prohibitins to regulate cardiolipin remodeling". Cell Metabolism 20 (1): 158–71. doi:10.1016/j.cmet.2014.04.016. PMID 24856930.
6. Davey KM, Parboosingh JS, McLeod DR, Chan A, Casey R, Ferreira P, et al. (May 2006). "Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition". Journal of Medical Genetics 43 (5): 385–93. doi:10.1136/jmg.2005.036657. PMC 2564511. PMID 16055927.
7. Ojala T, Polinati P, Manninen T, Hiippala A, Rajantie J, Karikoski R, Suomalainen A, Tyni T (Oct 2012). "New mutation of mitochondrial DNAJC19 causing dilated and noncompaction cardiomyopathy, anemia, ataxia, and male genital anomalies". Pediatric Research 72 (4): 432–7. doi:10.1038/pr.2012.92. PMID 22797137.
8. Koutras C, Braun JE (Jul 2014). "J protein mutations and resulting proteostasis collapse". Frontiers in Cellular Neuroscience 8: 191. doi:10.3389/fncel.2014.00191. PMID 25071450.
9. Mokranjac D, Bourenkov G, Hell K, Neupert W, Groll M (Oct 2006). "Structure and function of Tim14 and Tim16, the J and J-like components of the mitochondrial protein import motor". The EMBO Journal 25 (19): 4675–85. doi:10.1038/sj.emboj.7601334. PMID 16977310.

Further reading

• Sparkes R, Patton D, Bernier F (Apr 2007). "Cardiac features of a novel autosomal recessive dilated cardiomyopathic syndrome due to defective importation of mitochondrial protein". Cardiology in the Young 17 (2): 215–7. doi:10.1017/S1047951107000042. PMID 17244376.
• Davey KM, Parboosingh JS, McLeod DR, Chan A, Casey R, Ferreira P, Snyder FF, Bridge PJ, Bernier FP (May 2006). "Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition". Journal of Medical Genetics 43 (5): 385–93. doi:10.1136/jmg.2005.036657. PMC 2564511. PMID 16055927.
• Mokranjac D, Sichting M, Neupert W, Hell K (Oct 2003). "Tim14, a novel key component of the import motor of the TIM23 protein translocase of mitochondria". The EMBO Journal 22 (19): 4945–56. doi:10.1093/emboj/cdg485. PMC 204468. PMID 14517234.
• Taylor SW, Fahy E, Zhang B, Glenn GM, Warnock DE, Wiley S, Murphy AN, Gaucher SP, Capaldi RA, Gibson BW, Ghosh SS (Mar 2003). "Characterization of the human heart mitochondrial proteome". Nature Biotechnology 21 (3): 281–6. doi:10.1038/nbt793. PMID 12592411.
• Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ (Mar 2000). "Shotgun sequencing of the human transcriptome with ORF expressed sequence tags". Proceedings of the National Academy of Sciences of the United States of America 97 (7): 3491–6. doi:10.1073/pnas.97.7.3491. PMC 16267. PMID 10737800.
• Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.