Periodicity of leucine and tandem repetition of a 24-amino acid segment in the primary structure of leucine-rich alpha 2-glycoprotein of human serum.

The complete primary structure of the 3.1S leucine-rich alpha 2-glycoprotein (LRG) present in human plasma has been determined. This protein (Mr approximately 45,000) consists of a single polypeptide chain with one galactosamine and four glucosamine oligosaccharides attached. The polypeptide has two intrachain disulfide bonds and contains 312 amino acid residues of which 66 are leucine. The amino acid sequence can be exactly divided into 13 segments of 24 residues each, eight of which exhibit a periodic pattern in the occurrence of leucine, proline, and asparagine. The consensus sequence for the repeating tetracosapeptide unit is Pro-Xaa-Xaa-Leu-Leu-Xaa-Xaa-Xaa-X aa-Xaa-Leu-Xaa-Xaa-Leu-Xaa-Leu-Xaa-Xaa-Asn-Xaa-Leu-Xaa-Xaa-Leu. This periodicity suggests that the unique structure of LRG arose from a series of unequal crossovers of a precursor oligonucleotide sequence that encoded a building block rich in leucine. Overall, the amino acid sequence of LRG is not significantly homologous to the continuous sequence of any protein in the current data base. However, the consensus tetracosapeptide sequence shows strong homology to segments of many mitochondrial proteins, viral envelope proteins, and oncogene proteins that have a high leucine content and transmembrane domains. Tandem repetition of similar segments also occurs in apolipoproteins that have amphipathic helical potential. Prediction of the secondary structure by the Chou-Fasman rules and calculation of the hydrophilic/hydrophobic profile by several methods confirm the tandem repetition of largely hydrophobic structural units; these begin with a beta-turn that leads into an organized structure with alpha-helical or beta-sheet potential. These structural characteristics and the homology to mitochondrial proteins and apolipoproteins suggest that LRG is a membrane-derived or membrane-associated protein containing a series of domains capable of bipolar surface orientation.