title: An extracellular beta-propeller module predicted in lipoprotein and scavenger receptors, tyrosine kinases, epidermal growth factor precursor, and extracellular matrix components.
abstract: An abundant, widely dispersed, extracellular sequence repeat that contains a consensus YWTD motif is shown here to occur in groups of six contiguous repeats. Thirteen lines of evidence, including experimental and computational data, predict with p<3x10(-9) that the repeats do not form tandem domains, but rather each group of six repeats folds into a compact beta-propeller structure. The six beta-sheets are arranged about a 6-fold pseudosymmetry axis, and each repeat contributes loops to the faces surrounding the pseudosymmetry axis. Seven different endocytic receptors that contain from one to eight YWTD beta-propeller domains act as lipoprotein, vitellogenin, and scavenger receptors. In the low density lipoprotein receptor (LDLR), the many mutations in familial hypercholesterolaemia that map to the YWTD domain can now be interpreted. In the extracellular matrix component nidogen, the YWTD domain functions to bind laminin. Three YWTD domains and interspersed fibronectin type III (FN3) domains constitute almost the entire extracellular domain of the sevenless and c-ros receptor tyrosine kinases. YWTD domains often are bounded by epidermal growth factor (EGF) modules, including in the EGF precursor itself. YWTD beta-propellers have a circular folding pattern that brings neighboring modules into close proximity, and may have important consequences for the architecture of multi-domain proteins.
authors.affiliation: Department of Pathology, Center for Blood Research and Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. springer@sprsgi.med.harvard.edu
authors.forename: T A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D000595:Amino Acid Sequence; D004220:Disulfides / Q000737:chemistry; D004815:Epidermal Growth Factor / Q000737:chemistry*; D005091:Exons / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry*; D018110:Receptors, Lipoprotein / Q000737:chemistry*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D004220:Disulfides; D016326:Extracellular Matrix Proteins; D018110:Receptors, Lipoprotein; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases