Proteolipid protein (PLP), also named lipophilin, is the major structural protein of brain white matter. It accounts for more than 50% of myelin membrane proteins of the central nervous system (CNS) and is supposed to maintain the myelin structure and function.
Discovery
In 1951, it was shown that brain tissue and brain tumor tissue have been found to contain a new type of component - Proteolipides. PLPs are lipoproteins having as constituents a lipide moiety and a protein moiety, but, while other known lipoproteins are soluble in water or salt solutions, proteolipides are insoluble in water and soluble in chloroform- methanol mixtures; i.e., their solubilities are akin to those of lipides. It is to emphasize this special feature that the name proteolipides has been coined1.
Structural Characteristics
PLP consists of a 276-residue-long polypeptide chain with five strongly hydrophobic sequences of, linked by highly charged hydrophilic sequences. It has been propose that PLP is integrated into the lipid bilayer of myelin with the NH2 terminus and three positively charged hydrophilic loops oriented toward the extracytosolic side of the membrane, whereas one strongly negative hydrophilic loop and the positively charged COOH terminus cover the cytosolic side of the lipid bilayer. Basic myelinprotein remains protected against tryptic cleavage, which indicates its apposition to the cytosolic side of the membrane. These cleavage sites of trypsin support the suggested orientation of PLP in the myelin membrane and molecular arrangement2.
Mode of Action
PLP mediates winding and adhesion of phospholipid membranes but prevents their fusion: An experiment was conducted to investigate PLP’s putative adhesive function using purified PLP and reconstituted phospholipid vesicles made of either 100% phosphatidylcholine (PC), or a mixture of 92% PC and 8% phosphatidylserine (PS), by weight. PLP-induced changes in the phospholipid bilayer surfaces were directly examined by transmission electron microscopy. It was shown that, upon the introduction of PLP, larger lipid vesicles became smaller and unilamellar. At the PLP:lipid molar ratio of 1:20, vesicle membranes rolled onto themselves forming ‘croissant’-like structures that subsequently adhered to each other. The phenomena of PLP-induced bilayer rolling and adhesion were dependent on the concentration of PLP and the period of incubation, but were independent of the presence of calcium and types of phospholipids (PC or PC:PS). Furthermore, the presence of PLP in the lipid bilayers prevented the fusion of membranes. This shows that PLP can induce membrane ‘winding’ while preventing the fusion of adjacent lipid bilayers. Hence, provide direct evidence for PLP’s suspected function of membrane adhesion, and also suggest that PLP could potentially play a role in the formation of the myelin sheath.
Functions
Myelin proteolipid protein forms a complex with integrins and may participate in integrin receptor signaling in oligodendrocytes: A new role for the myelin proteolipid protein (PLP) has been identified, in studies showing PLP interaction with signaling proteins in oligodendrocytes. In particular, these studies suggest that the PLP protein may be involved in signaling through integrins in oligodendrocytes. Stimulation of muscarinic acetylcholine receptors on oligodendrocytes induced formation of a tripartite complex containing PLP, calreticulin, and a?-integrin. PLP interacted directly with the cytoplasmic domain of the a?-integrin. It has been shown that Complex formation was mediated by phospholipase C and Ca2+ binding to the high affinity binding site on calreticulin. Furthermore, this complex appears important for binding of fibronectin to oligodendrocytes. These data establish a novel function for PLP as a part of the integrin signaling complex in oligodendrocytes and suggest that neurotransmitter-mediated integrin receptor signaling may be involved in myelinogenesis4.
PLP and its role in the nervous system: A variety of mutations (missense mutations, deletions, and duplications) of the X-linked PLP gene cause the heterogeneous syndromes of Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia (SPG) in man and similar dysmyelinating disorders in a range of animal species.
Missense mutations cause a predicted alteration in primary structure of the encoded proteins and are generally associated with early onset of signs and generalised dysmyelination. The severity of the phenotype varies according to the particular codon involved. There is some evidence that the dysmyelination results from the altered protein acquiring a novel function deleterious to the oligodendrocyte's function. Transgenic mice carrying extra copies of the PLP gene provide a valid model of PMD/SPG due to gene duplication. Depending on the gene dosage, the phenotype can vary from early onset of severe and lethal dysmyelination through to a very late onset of a tract-specific demyelination and axonal degeneration5.
References
1.Folch J, Lees M (1951) Proteolipids, a new type of tissue lipoproteins. Their isolation from brain. J. Biol. Chem., 191(2):807-817.
2.Stoffel W, Hillen H, Giersiefen H. (1984) Structure and molecular arrangement of proteolipid protein of central nervous system myelin. Proc. Nati. Acad. Sci., 81(16):5012-5016.
3.Palaniyar N, Semotok JL, Wood DD, Moscarello MA, Harauz G. (1998). Human proteolipid protein (PLP) mediates winding and adhesion of phospholipid membranes but prevents their fusion. Biochim. Biophys. Acta., 1415 (1): 85-100.
4.Gudz TI, Schneider TE, Haas TA, Macklin WB. (2002). Myelin Proteolipid Protein Forms a Complex with Integrins and May Participate in Integrin Receptor Signaling in Oligodendrocytes. J Neurosci., 22 (17):7398-7407.
5.Griffiths I, Klugmann M, Anderson T, Thomson C, Vouyiouklis D, Nave KA (1998). Current concepts of PLP and its role in the nervous system. Microsc. Res. Tech., 41(5): 344-358
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