title: Folding and function of the myelin proteins from primary sequence data.
abstract: To explain how the myelin proteins are involved in the organization and function of the myelin sheath requires knowing their molecular structures. Except for P2 basic protein of PNS myelin, however, their structures are not yet known. As an aid to predicting their molecular folding and possible functions, we have developed a FORTRAN program to analyze the primary sequence data for proteins, and have applied this to the myelin proteins in particular. In this program, propensities for the secondary structure conformations as well as physical-chemical parameters are assigned to the amino acids and the pattern of these parameters is examined by calculating their average values, autocorrelation functions and Fourier transforms. To compare two proteins, their sequences are aligned using a unitary scoring matrix, and homologies are searched by plotting a two-dimensional map of the correlation coefficients. Comparison of the corresponding myelin basic proteins (MBP) and P0 glycoproteins (P0) for rodent and shark showed that the conserved residues included most of the amino acids which were predicted to form the alpha or beta conformations, while the altered residues were mainly in the hydrophilic and turn or coil regions. In both rodent and shark the putative extracellular domain of P0 glycoprotein displayed consecutive peaks of beta propensity similar to that for the immunoglobulins, while the cytoplasmic domain showed alpha-beta-alpha folding. To trace the immunoglobulin fold along the P0 sequence, we compared the beta propensity curve of P0 with that of the immunoglobulin M603, whose three-dimensional structure has been determined. We propose that the flat beta-sheets of P0 are orientated parallel to the membrane surface to facilitate their homotypic interaction in the extracellular space. An extra beta-fold in the extracellular domain of shark P0 compared with rodent P0 was found, and this may result in a greater attraction between the apposed extracellular surfaces and may account for a smaller extracellular space as measured by x-ray diffraction. A computer search of the myelin protein sequences for functional motifs revealed sites for N-glycosylation, phosphorylation, nucleotide binding, and certain enzyme activities. We note especially that there are potential nucleotide binding sites in proteolipid protein (PLP), MBP and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP). This is consistent with the experimental observations that PLP acts like an ionophore or proton channel when reconstituted into planar lipid bilayers, MBP binds GTP, and CNP catalyzes in vitro the hydrolysis of 2',3'-nucleotides into corresponding 2'-nucleotides.
authors.affiliation: Children's Hospital, Boston, MA 02115.
authors.forename: H
authors.initials: H
authors.lastname: Inouye
authors.forename: D A
authors.initials: DA
authors.lastname: Kirschner
mesh_terms: D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D000939:Epitopes / Q000235:genetics; D051379:Mice / Q000235:genetics; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000235:genetics* / Q000378:metabolism; D018993:Myelin P0 Protein; D009185:Myelin Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018991:Myelin Proteolipid Protein; D018992:Myelin-Associated Glycoprotein; D010727:Phosphoric Diester Hydrolases; D011485:Protein Binding; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D051381:Rats; D012377:Rodentia; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D012984:Software; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D016229:Amyloid beta-Peptides; D000939:Epitopes; D004676:Myelin Basic Protein; D018993:Myelin P0 Protein; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D018992:Myelin-Associated Glycoprotein; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D010727:Phosphoric Diester Hydrolases; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; C571338:Cnp protein, mouse; C571339:Cnp protein, rat