PMP2 Human

PMP2 is a 14.5 kDa protein composed of 131 amino acids with a net positive charge. The protein has a barrel-shaped structure that allows it to bind fatty acids within its cavity. The crystal structure of human PMP2 has been determined to a resolution of 1.85 Å, revealing a fatty acid molecule, modeled as palmitate, bound inside the protein . This structure is similar to that of the protein in solution, as confirmed by synchrotron radiation studies .

The protein is highly abundant in the myelin sheath of the PNS, constituting up to 15% of the total protein content . It is also present in smaller amounts in the central nervous system (CNS), particularly in the spinal cord and brain stem . PMP2 plays a structural role in the myelin membrane, contributing to the stability and compaction of the myelin sheath. It is also involved in membrane stacking and lipid transfer, which are essential for the proper functioning of myelinated nerves .

Traditionally, myelin proteins were purified directly from vertebrate nervous tissues. However, recombinant techniques have enabled the controlled production of homogeneous samples of myelin proteins, including PMP2, with or without desired mutations . Recombinant human PMP2 is produced using these techniques, allowing for large-scale purification and detailed structural and functional studies .

Mutations in the gene encoding PMP2 have been linked to Charcot-Marie-Tooth (CMT) disease, a common inherited neuromuscular disorder characterized by clinical, genetic, and pathomechanistic heterogeneity . CMT affects the myelin sheath, leading to inefficient compaction and insulation of axons, resulting in reduced nerve conduction velocities . Several mutations in PMP2 have been identified, including p.Ile43Asn, p.Thr51Pro, and p.Ile52Thr, which cluster together and affect highly conserved amino acid residues . These mutations are associated with a childhood-onset polyneuropathy with variable patterns of demyelination and slow progression .

Ongoing research aims to further elucidate the structure and function of PMP2 and its role in myelin biology. Understanding the molecular mechanisms underlying PMP2-related neuropathies could lead to the development of targeted therapies for CMT and other myelin-related disorders. Additionally, the use of recombinant techniques to produce PMP2 and other myelin proteins continues to advance our knowledge of myelin structure and function, paving the way for new therapeutic approaches.