Insulin and epidermal growth factor receptors contain the cysteine repeat motif found in the tumor necrosis factor receptor.
The insulin receptor (INSR) and epidermal growth factor receptor (EGFR) are representatives of two structurally related subfamilies of tyrosine kinase receptors. Using the Wisconsin GCG sequence analysis programs, we have demonstrated that the cysteine-rich regions of INSR and EGFR conform to the structural motif found in the tumor necrosis factor receptor (TNFR) family. The study also revealed that these regions were not composed of simple repeats of eight cysteine residues as previously proposed and that the second Cys-rich region of EGFR contained one fewer TNFR repeat than the first. The sequence alignments identified two cysteine residues in INSR that could be responsible for the additional disulfide bonds known to be involved in dimer formation. The published data on the alignments for the fibronectin type III repeat region of the INSR together with previous cysteine mutagenesis studies indicated that there were two disulfide bonds linking the alpha and beta chains of the INSR, but only one alpha-beta linkage in the insulin-like growth factor 1 receptor (IG1R). Database searches and sequence alignments showed that the TNFR motif is also found in the cysteine-rich repeats of laminins and the noncatalytic domains of furin-like proteases. If the starting position of the repeat is altered the characteristic laminin repeat of eight cysteine residues can be shown to consist of a TNFR-like motif fused to the last half of an EGF-like repeat. The overlapping regions of these two motifs are known to have identical disulfide bonding patterns and similar protein folds.
Ward
C W
CW
CSIRO, Division of Biomolecular Engineering, Parkville, Victoria, Australia.
Hoyne
P A
PA
Flegg
R H
RH
D000595:Amino Acid Sequence; D000818:Animals; D003545:Cysteine / Q000737:chemistry*; D016208:Databases, Factual; D004220:Disulfides / Q000737:chemistry; D066246:ErbB Receptors / Q000235:genetics*; D045683:Furin; D007797:Laminin / Q000235:genetics; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D016415:Sequence Alignment; D012984:Software; D013381:Subtilisins / Q000235:genetics; D019063:Tenascin / Q000235:genetics
D004220:Disulfides; D007797:Laminin; D009419:Nerve Tissue Proteins; D018124:Receptors, Tumor Necrosis Factor; D019063:Tenascin; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D013381:Subtilisins; D045683:Furin; D003545:Cysteine