Mitochondrial import inner membrane translocase subunit TIM14 is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

that in humans is encoded by the ''DNAJC19''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

on chromosome 3. TIM14 belongs to the DnaJ family, which has been involved in Hsp40/Hsp70 chaperone systems. As a

mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used t ...

chaperone, TIM14 functions as part of the TIM23 complex import motor to facilitate the import of nuclear-encoded proteins into the mitochondria. TIM14 also complexes with

prohibitin Prohibitin, also known as PHB, is a protein that in humans is encoded by the ''PHB'' gene. The ''Phb'' gene has also been described in animals, fungi, plants, and unicellular eukaryotes. Prohibitins are divided in two classes, termed Type-I and T ...

complexes to regulate mitochondrial

morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...

, and has been implicated in

dilated cardiomyopathy Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. Co ...

with ataxia.

Structure

The ''DNAJC19'' gene is located on the

q arm In genetics, a locus (plural loci) is a specific, fixed position on a chromosome where a particular gene or genetic marker is located. Each chromosome carries many genes, with each gene occupying a different position or locus; in humans, the tota ...

chromosome 3 Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA in ...

at position 26.33 and it spans 6,065 base pairs. The ''DNAJC19'' gene produces a 6.29 kDa protein composed of 59

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

. 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 The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

rather than the

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

, and the

transmembrane A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequent ...

domain confers membrane-bound localization for TIM14 while other DNAJ proteins are cytosolic. TIM14

ortholog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a s ...

s in other species, such as the yeast Tim14 and Mdj2p proteins, confirm localization to the mitochondrial inner membrane.

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 ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...

activity to power this transport. Additionally, TIM14 helps regulate mitochondrial morphology by complexing with prohibitins to perform disphosphoglycerolipid

cardiolipin Cardiolipin (IUPAC name 1,3-bis(''sn''-3’-phosphatidyl)-''sn''-glycerol) is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition. It can also be found in the membranes of most ...

(CL) remodeling. CL is a key

phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

in mitochondrial membranes that modulates the fusion and fission of mitochondrial membranes, as well as mitophagy and

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

Clinical significance

Defects in DNAJC19 have been observed primarily in cases of

with ataxia (DCMA), though it has also been associated with

growth failure Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...

, 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. In the clinic, DNAJC19 mutations can be detected by screening for elevated levels of

3-methylglutaconic acid 3-Methylglutaconic acid is a glutarate which builds up in the urine in 3-methylglutaconic aciduria 3-Methylglutaconic aciduria (MGA) is any of at least five metabolic disorders that impair the body's ability to make energy in the mitochondria. A ...

, mitochondrial distress, dilated cardiomyopathy, prolongation of the

QT interval The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave, and approximates to the time taken ...

in the electrocardiogram, and

cerebellar ataxia Cerebellar ataxia is a form of ataxia originating in the cerebellum. Non-progressive congenital ataxia (NPCA) is a classical presentation of cerebral ataxias. Cerebellar ataxia can occur as a result of many diseases and may present with sympto ...

Interactions

TIM14 interacts with: * TIMM44, * mtHsp70, * TIMM16/ PAM16, and *

PHB2 Prohibitin-2 is a protein that in humans is encoded by the ''PHB2'' gene. Interactions PHB2 has been shown to Protein-protein interaction, interact with PTMA. References Further reading

* * * * * * * * * * * * * * * * * {{protein-stub ...