A New Functional Motif in Hox Domain-containing Ceramide Synthases

By A. Mesika, Shifra Ben-Dor, Elad L. Laviad, A. Futerman. 2007

67 citations recorded by the source corpus.

Ceramide is synthesized in mammals by a family of ceramide synthases (CerS) each of which uses a relatively restricted set of fatty acyl-CoAs for N-acylation of the sphingoid long chain base (Pewzner-Jung, Y., Ben-Dor, S., and Futerman, A. H. (2006) J. Biol. Chem. 281, 25001-25005). CerS are characterized by two functional domains, the Tram-Lag-CLN8 (TLC) domain and the homeobox (Hox) domain, which is found in all mammalian CerS except CerS1. We now demonstrate that the majority of the Hox domain is not required for CerS activity since its deletion in CerS5 does not affect activity. Subsequently, we define a highly conserved new motif of 12 amino acid residues that flanks the Hox and TLC domains but is not part of the TLC domain, which is essential for CerS5 and CerS6 activity. Two positively charged residues in this domain, one of which is conserved in all putative CerS in all organisms, are essential for activity since site-directed mutagenesis of either (Lys-134 and Lys-140 in CerS5) results in an ∼50% loss of activity, whereas mutation of both leads to a complete loss of activity. Because this region is conserved across species, we propose that it plays a previously unidentified and essential role in CerS activity and can be used as a new motif to define Hox domain-containing CerS.

Subfields: Biochemistry, Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biochemistry

1. Michal Levy
2. B. Ogretmen
3. S. Saddoughi
4. P. Song
5. A. Futerman

In Molecular Biology

1. Michal Levy
2. B. Ogretmen
3. A. Futerman
4. S. Saddoughi
5. P. Song
6. M. Affolter
7. T. Bürglin
8. Yusuf A. Hannun

Citations in the corpus

• Mammalian Ceramide Synthases (2010, background): “tively charged conserved residues (K134, K140) in this region critical for catalytic activity (25).”
• Roles of bioactive sphingolipids in cancer biology and therapeutics. (2008, background): “All of the CerS proteins, except CerS1, contain a homeobox transcription factor HOX domain found at the N-terminus (Mesika et al., 2007) except for CerS1, which might be important for the enzymatic activity of CerS2–6.”
• Homeodomain proteins: an update (2015, background): “Experimentally, virtually the complete HD could be deleted without affecting function, although residues at the very end of the HD and in the linker between the HD and the second TM region are required for function (Mesika et al. 2007).”
• The Human Transcription Factors. (2018, unknown): “The CERS/ Lass-type Homeodomains, for example, are not likely to be DNA-binding proteins at all; they instead appear to have been co-opted to function in sphingolipid synthesis (Mesika et al., 2007).”