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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

HHpred comparison E-values. The numbers correspond to E-values from HHpred (Söding et al., 2005) profile searches against a Pfam profile database which includes profiles that represent families shown in the figure. Profile-to-profile matches were evaluated in terms of an E-value, which is the expected number of non-homologous proteins with a score higher than that obtained for the database match. An E-value much lower than one indicates statistical significance. Solid lines represent statistically significant sequence similarity relationships, e.g., the MAC30/TMEM97 family calibrated profile finds with 0.003 and 0.03 E-values the profiles of EBP family and TM6SF first EXPERA repeat, respectively. The black dotted line between TM6SF second EXPERA domain repeat and EBP shows the unique relationship found with a non-highly significant value (E-value 1.2). The sequence similarity between TM6SF (second EXPERA domain repeat) and MAC30/TMEM97 families (presented inside the blue dotted oval) was already described in a DUF (Domain of Unknown Function) entry of Pfam (DUF2781, Pfam family identification: PF10914) (Bateman et al., 2010; Punta et al., 2012).
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Figure 4: HHpred comparison E-values. The numbers correspond to E-values from HHpred (Söding et al., 2005) profile searches against a Pfam profile database which includes profiles that represent families shown in the figure. Profile-to-profile matches were evaluated in terms of an E-value, which is the expected number of non-homologous proteins with a score higher than that obtained for the database match. An E-value much lower than one indicates statistical significance. Solid lines represent statistically significant sequence similarity relationships, e.g., the MAC30/TMEM97 family calibrated profile finds with 0.003 and 0.03 E-values the profiles of EBP family and TM6SF first EXPERA repeat, respectively. The black dotted line between TM6SF second EXPERA domain repeat and EBP shows the unique relationship found with a non-highly significant value (E-value 1.2). The sequence similarity between TM6SF (second EXPERA domain repeat) and MAC30/TMEM97 families (presented inside the blue dotted oval) was already described in a DUF (Domain of Unknown Function) entry of Pfam (DUF2781, Pfam family identification: PF10914) (Bateman et al., 2010; Punta et al., 2012).

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)

HHpred comparison E-values. The numbers correspond to E-values from HHpred (Söding et al., 2005) profile searches against a Pfam profile database which includes profiles that represent families shown in the figure. Profile-to-profile matches were evaluated in terms of an E-value, which is the expected number of non-homologous proteins with a score higher than that obtained for the database match. An E-value much lower than one indicates statistical significance. Solid lines represent statistically significant sequence similarity relationships, e.g., the MAC30/TMEM97 family calibrated profile finds with 0.003 and 0.03 E-values the profiles of EBP family and TM6SF first EXPERA repeat, respectively. The black dotted line between TM6SF second EXPERA domain repeat and EBP shows the unique relationship found with a non-highly significant value (E-value 1.2). The sequence similarity between TM6SF (second EXPERA domain repeat) and MAC30/TMEM97 families (presented inside the blue dotted oval) was already described in a DUF (Domain of Unknown Function) entry of Pfam (DUF2781, Pfam family identification: PF10914) (Bateman et al., 2010; Punta et al., 2012).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: HHpred comparison E-values. The numbers correspond to E-values from HHpred (Söding et al., 2005) profile searches against a Pfam profile database which includes profiles that represent families shown in the figure. Profile-to-profile matches were evaluated in terms of an E-value, which is the expected number of non-homologous proteins with a score higher than that obtained for the database match. An E-value much lower than one indicates statistical significance. Solid lines represent statistically significant sequence similarity relationships, e.g., the MAC30/TMEM97 family calibrated profile finds with 0.003 and 0.03 E-values the profiles of EBP family and TM6SF first EXPERA repeat, respectively. The black dotted line between TM6SF second EXPERA domain repeat and EBP shows the unique relationship found with a non-highly significant value (E-value 1.2). The sequence similarity between TM6SF (second EXPERA domain repeat) and MAC30/TMEM97 families (presented inside the blue dotted oval) was already described in a DUF (Domain of Unknown Function) entry of Pfam (DUF2781, Pfam family identification: PF10914) (Bateman et al., 2010; Punta et al., 2012).
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