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TM6SF2 and MAC30, new enzyme homologs in sterol metabolism and common metabolic disease.

Sanchez-Pulido L, Ponting CP - Front Genet (2014)

Bottom Line: We identified a new domain, the EXPERA domain, which is conserved among TM6SF, MAC30/TMEM97 and EBP (D8, D7 sterol isomerase) protein families.EBP mutations are the cause of chondrodysplasia punctata 2 X-linked dominant (CDPX2), also known as Conradi-Hünermann-Happle syndrome, a defective cholesterol biosynthesis disorder.Our analysis of evolutionary conservation among EXPERA domain-containing families and the previously suggested catalytic mechanism for the EBP enzyme, indicate that TM6SF and MAC30/TMEM97 families are both highly likely to possess, as for the EBP family, catalytic activity as sterol isomerases.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford Oxford, UK.

ABSTRACT
Carriers of the Glu167Lys coding variant in the TM6SF2 gene have recently been identified as being more susceptible to non-alcoholic fatty liver disease (NAFLD), yet exhibit lower levels of circulating lipids and hence are protected against cardiovascular disease. Despite the physiological importance of these observations, the molecular function of TM6SF2 remains unknown, and no sequence similarity with functionally characterized proteins has been identified. In order to trace its evolutionary history and to identify functional domains, we embarked on a computational protein sequence analysis of TM6SF2. We identified a new domain, the EXPERA domain, which is conserved among TM6SF, MAC30/TMEM97 and EBP (D8, D7 sterol isomerase) protein families. EBP mutations are the cause of chondrodysplasia punctata 2 X-linked dominant (CDPX2), also known as Conradi-Hünermann-Happle syndrome, a defective cholesterol biosynthesis disorder. Our analysis of evolutionary conservation among EXPERA domain-containing families and the previously suggested catalytic mechanism for the EBP enzyme, indicate that TM6SF and MAC30/TMEM97 families are both highly likely to possess, as for the EBP family, catalytic activity as sterol isomerases. This unexpected prediction of enzymatic functions for TM6SF and MAC30/TMEM97 is important because it now permits detailed experiments to investigate the function of these key proteins in various human pathologies, from cardiovascular disease to cancer.

No MeSH data available.


Related in: MedlinePlus

(A) Mapping alanine-scanning mutagenesis and known disease causing missense mutations in the EBP model. Alanine-scanning (Moebius et al., 1999) identified 11 residues as major determinants of EBP catalytic activity (His77, Glu81, Trp102, Tyr105, Asp109, Arg111, Tyr112, Glu123, Thr126, Asn194, and Trp197; here renumbered to the current EBP_HUMAN SwissProt entry numbering by subtracting one to the number of each position). Four (orange points) are present in exactly the same positions as are disease associated mutations (H76Y, E80K, R110Q, and W196S) and the remaining seven (W101, Y104, D108, Y111, E122, T125, and N193) (yellow points) are located in the vicinity of disease associated mutations (fewer than five residues-distant). Mapped CDPX2 disease causing missense mutations (red points), derived from Human Gene Mutation Database (HGMD) and PubMed analysis (Stenson et al., 2003), are: M1I (Steijlen et al., 2007), M1V (Hello et al., 2010), R62W (Herman et al., 2002), L66P (Whittock et al., 2003), C67R (Morice-Picard et al., 2011), W68C (Lambrecht et al., 2014), C72Y (Herman et al., 2002), I75N (Barboza-Cerda et al., 2014), H76Y (Umekoji et al., 2008), E80K (Braverman et al., 1999; Ikegawa et al., 2000; Aughton et al., 2003), W82C (Has et al., 2002; Shirahama et al., 2003), S98F (Tysoe et al., 2008), S98P (Tysoe et al., 2008), E103K (Kolb-Mäurer et al., 2008), G107R (Derry et al., 1999), R110Q (Derry et al., 1999; Hou, 2013), V119G (Non-lethal) (Cañueto et al., 2012; Bode et al., 2013), G130V (Herman et al., 2002), S133R (Braverman et al., 1999; Derry et al., 1999), R147G (Becker et al., 2001), R147H (Braverman et al., 1999; Has et al., 2000; Ikegawa et al., 2000; Shirahama et al., 2003), G157S (Herman et al., 2002), D162H (Whittock et al., 2003), L164P (Cañueto et al., 2012), Y165C (Shirahama et al., 2003), G173R (Herman et al., 2002), W196S (Herman et al., 2002), L203P (Has et al., 2002), D206Y (Ausavarat et al., 2008). L18P and W47C (Milunsky et al., 2003; Furtado et al., 2010) present a less severe phenotype called MEND (Male EBP Disorder with Neurological Defects) syndrome (Arnold et al., 2012). (B) Reaction catalyzed by EBP. Cholesterol carbon atoms C7, C8, and C9 are label.
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Figure 2: (A) Mapping alanine-scanning mutagenesis and known disease causing missense mutations in the EBP model. Alanine-scanning (Moebius et al., 1999) identified 11 residues as major determinants of EBP catalytic activity (His77, Glu81, Trp102, Tyr105, Asp109, Arg111, Tyr112, Glu123, Thr126, Asn194, and Trp197; here renumbered to the current EBP_HUMAN SwissProt entry numbering by subtracting one to the number of each position). Four (orange points) are present in exactly the same positions as are disease associated mutations (H76Y, E80K, R110Q, and W196S) and the remaining seven (W101, Y104, D108, Y111, E122, T125, and N193) (yellow points) are located in the vicinity of disease associated mutations (fewer than five residues-distant). Mapped CDPX2 disease causing missense mutations (red points), derived from Human Gene Mutation Database (HGMD) and PubMed analysis (Stenson et al., 2003), are: M1I (Steijlen et al., 2007), M1V (Hello et al., 2010), R62W (Herman et al., 2002), L66P (Whittock et al., 2003), C67R (Morice-Picard et al., 2011), W68C (Lambrecht et al., 2014), C72Y (Herman et al., 2002), I75N (Barboza-Cerda et al., 2014), H76Y (Umekoji et al., 2008), E80K (Braverman et al., 1999; Ikegawa et al., 2000; Aughton et al., 2003), W82C (Has et al., 2002; Shirahama et al., 2003), S98F (Tysoe et al., 2008), S98P (Tysoe et al., 2008), E103K (Kolb-Mäurer et al., 2008), G107R (Derry et al., 1999), R110Q (Derry et al., 1999; Hou, 2013), V119G (Non-lethal) (Cañueto et al., 2012; Bode et al., 2013), G130V (Herman et al., 2002), S133R (Braverman et al., 1999; Derry et al., 1999), R147G (Becker et al., 2001), R147H (Braverman et al., 1999; Has et al., 2000; Ikegawa et al., 2000; Shirahama et al., 2003), G157S (Herman et al., 2002), D162H (Whittock et al., 2003), L164P (Cañueto et al., 2012), Y165C (Shirahama et al., 2003), G173R (Herman et al., 2002), W196S (Herman et al., 2002), L203P (Has et al., 2002), D206Y (Ausavarat et al., 2008). L18P and W47C (Milunsky et al., 2003; Furtado et al., 2010) present a less severe phenotype called MEND (Male EBP Disorder with Neurological Defects) syndrome (Arnold et al., 2012). (B) Reaction catalyzed by EBP. Cholesterol carbon atoms C7, C8, and C9 are label.

Mentions: By iteratively improving the phyletic coverage in each protein family using HMMer database searches (Eddy, 1996), we obtained statistical significance from profile-profile comparisons that link these three sequence families (specifically, the two TM6SF repeats and the single MAC30/TMEM97 repeat) to the Emopamil binding protein (EBP) family (Figures 3, 4). The significance of these sequence similarities, their common transmembrane helix configuration, and their shared predicted C-terminal ER retention signal (Figures 1, 2) (Jackson et al., 1990) imply that these domains are homologous, having derived from a common evolutionary ancestor. We name this four transmembrane region the EXPERA (EXPanded EBP superfamily) domain.


TM6SF2 and MAC30, new enzyme homologs in sterol metabolism and common metabolic disease.

Sanchez-Pulido L, Ponting CP - Front Genet (2014)

(A) Mapping alanine-scanning mutagenesis and known disease causing missense mutations in the EBP model. Alanine-scanning (Moebius et al., 1999) identified 11 residues as major determinants of EBP catalytic activity (His77, Glu81, Trp102, Tyr105, Asp109, Arg111, Tyr112, Glu123, Thr126, Asn194, and Trp197; here renumbered to the current EBP_HUMAN SwissProt entry numbering by subtracting one to the number of each position). Four (orange points) are present in exactly the same positions as are disease associated mutations (H76Y, E80K, R110Q, and W196S) and the remaining seven (W101, Y104, D108, Y111, E122, T125, and N193) (yellow points) are located in the vicinity of disease associated mutations (fewer than five residues-distant). Mapped CDPX2 disease causing missense mutations (red points), derived from Human Gene Mutation Database (HGMD) and PubMed analysis (Stenson et al., 2003), are: M1I (Steijlen et al., 2007), M1V (Hello et al., 2010), R62W (Herman et al., 2002), L66P (Whittock et al., 2003), C67R (Morice-Picard et al., 2011), W68C (Lambrecht et al., 2014), C72Y (Herman et al., 2002), I75N (Barboza-Cerda et al., 2014), H76Y (Umekoji et al., 2008), E80K (Braverman et al., 1999; Ikegawa et al., 2000; Aughton et al., 2003), W82C (Has et al., 2002; Shirahama et al., 2003), S98F (Tysoe et al., 2008), S98P (Tysoe et al., 2008), E103K (Kolb-Mäurer et al., 2008), G107R (Derry et al., 1999), R110Q (Derry et al., 1999; Hou, 2013), V119G (Non-lethal) (Cañueto et al., 2012; Bode et al., 2013), G130V (Herman et al., 2002), S133R (Braverman et al., 1999; Derry et al., 1999), R147G (Becker et al., 2001), R147H (Braverman et al., 1999; Has et al., 2000; Ikegawa et al., 2000; Shirahama et al., 2003), G157S (Herman et al., 2002), D162H (Whittock et al., 2003), L164P (Cañueto et al., 2012), Y165C (Shirahama et al., 2003), G173R (Herman et al., 2002), W196S (Herman et al., 2002), L203P (Has et al., 2002), D206Y (Ausavarat et al., 2008). L18P and W47C (Milunsky et al., 2003; Furtado et al., 2010) present a less severe phenotype called MEND (Male EBP Disorder with Neurological Defects) syndrome (Arnold et al., 2012). (B) Reaction catalyzed by EBP. Cholesterol carbon atoms C7, C8, and C9 are label.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263179&req=5

Figure 2: (A) Mapping alanine-scanning mutagenesis and known disease causing missense mutations in the EBP model. Alanine-scanning (Moebius et al., 1999) identified 11 residues as major determinants of EBP catalytic activity (His77, Glu81, Trp102, Tyr105, Asp109, Arg111, Tyr112, Glu123, Thr126, Asn194, and Trp197; here renumbered to the current EBP_HUMAN SwissProt entry numbering by subtracting one to the number of each position). Four (orange points) are present in exactly the same positions as are disease associated mutations (H76Y, E80K, R110Q, and W196S) and the remaining seven (W101, Y104, D108, Y111, E122, T125, and N193) (yellow points) are located in the vicinity of disease associated mutations (fewer than five residues-distant). Mapped CDPX2 disease causing missense mutations (red points), derived from Human Gene Mutation Database (HGMD) and PubMed analysis (Stenson et al., 2003), are: M1I (Steijlen et al., 2007), M1V (Hello et al., 2010), R62W (Herman et al., 2002), L66P (Whittock et al., 2003), C67R (Morice-Picard et al., 2011), W68C (Lambrecht et al., 2014), C72Y (Herman et al., 2002), I75N (Barboza-Cerda et al., 2014), H76Y (Umekoji et al., 2008), E80K (Braverman et al., 1999; Ikegawa et al., 2000; Aughton et al., 2003), W82C (Has et al., 2002; Shirahama et al., 2003), S98F (Tysoe et al., 2008), S98P (Tysoe et al., 2008), E103K (Kolb-Mäurer et al., 2008), G107R (Derry et al., 1999), R110Q (Derry et al., 1999; Hou, 2013), V119G (Non-lethal) (Cañueto et al., 2012; Bode et al., 2013), G130V (Herman et al., 2002), S133R (Braverman et al., 1999; Derry et al., 1999), R147G (Becker et al., 2001), R147H (Braverman et al., 1999; Has et al., 2000; Ikegawa et al., 2000; Shirahama et al., 2003), G157S (Herman et al., 2002), D162H (Whittock et al., 2003), L164P (Cañueto et al., 2012), Y165C (Shirahama et al., 2003), G173R (Herman et al., 2002), W196S (Herman et al., 2002), L203P (Has et al., 2002), D206Y (Ausavarat et al., 2008). L18P and W47C (Milunsky et al., 2003; Furtado et al., 2010) present a less severe phenotype called MEND (Male EBP Disorder with Neurological Defects) syndrome (Arnold et al., 2012). (B) Reaction catalyzed by EBP. Cholesterol carbon atoms C7, C8, and C9 are label.
Mentions: By iteratively improving the phyletic coverage in each protein family using HMMer database searches (Eddy, 1996), we obtained statistical significance from profile-profile comparisons that link these three sequence families (specifically, the two TM6SF repeats and the single MAC30/TMEM97 repeat) to the Emopamil binding protein (EBP) family (Figures 3, 4). The significance of these sequence similarities, their common transmembrane helix configuration, and their shared predicted C-terminal ER retention signal (Figures 1, 2) (Jackson et al., 1990) imply that these domains are homologous, having derived from a common evolutionary ancestor. We name this four transmembrane region the EXPERA (EXPanded EBP superfamily) domain.

Bottom Line: We identified a new domain, the EXPERA domain, which is conserved among TM6SF, MAC30/TMEM97 and EBP (D8, D7 sterol isomerase) protein families.EBP mutations are the cause of chondrodysplasia punctata 2 X-linked dominant (CDPX2), also known as Conradi-Hünermann-Happle syndrome, a defective cholesterol biosynthesis disorder.Our analysis of evolutionary conservation among EXPERA domain-containing families and the previously suggested catalytic mechanism for the EBP enzyme, indicate that TM6SF and MAC30/TMEM97 families are both highly likely to possess, as for the EBP family, catalytic activity as sterol isomerases.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford Oxford, UK.

ABSTRACT
Carriers of the Glu167Lys coding variant in the TM6SF2 gene have recently been identified as being more susceptible to non-alcoholic fatty liver disease (NAFLD), yet exhibit lower levels of circulating lipids and hence are protected against cardiovascular disease. Despite the physiological importance of these observations, the molecular function of TM6SF2 remains unknown, and no sequence similarity with functionally characterized proteins has been identified. In order to trace its evolutionary history and to identify functional domains, we embarked on a computational protein sequence analysis of TM6SF2. We identified a new domain, the EXPERA domain, which is conserved among TM6SF, MAC30/TMEM97 and EBP (D8, D7 sterol isomerase) protein families. EBP mutations are the cause of chondrodysplasia punctata 2 X-linked dominant (CDPX2), also known as Conradi-Hünermann-Happle syndrome, a defective cholesterol biosynthesis disorder. Our analysis of evolutionary conservation among EXPERA domain-containing families and the previously suggested catalytic mechanism for the EBP enzyme, indicate that TM6SF and MAC30/TMEM97 families are both highly likely to possess, as for the EBP family, catalytic activity as sterol isomerases. This unexpected prediction of enzymatic functions for TM6SF and MAC30/TMEM97 is important because it now permits detailed experiments to investigate the function of these key proteins in various human pathologies, from cardiovascular disease to cancer.

No MeSH data available.


Related in: MedlinePlus