Structures and molecular functions of myelin proteins associated with leukodystrophy and peripheral neuropathies
Thesis event information
Date and time of the thesis defence
Place of the thesis defence
Lecture hall A101 (fysiatria), Aapistie 7A
Topic of the dissertation
Structures and molecular functions of myelin proteins associated with leukodystrophy and peripheral neuropathies
Doctoral candidate
Master of Science Maiju Uusitalo
Faculty and unit
University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, Protein and Structural Biology
Subject of study
Biochemistry
Opponent
Professor Judith Peters, Université Grenoble Alpes
Custos
Professor Petri Kursula, University of Oulu
Solving the structure of myelin proteins offers new opportunities for understanding nervous system diseases
The structure study of myelin proteins provides an understanding of the effect of mutations causing neuropathies on the structure and function of proteins in the cell, the onset of symptoms and the treatment of diseases.
The axons of neurons in the central and peripheral nervous system are protected by myelin. Myelin promotes the conduction speed of the nerve impulse in the axons. Myelin proteins enable cell movement, signal transmission and immune defense. Mutations in myelin proteins cause hereditary diseases that degenerate myelin, such as leukodystrophy and types of Charcot-Marie-Tooth disease of varying severity. The spectrum of symptoms and severity of symptoms vary greatly between patients.
This dissertation compared the structure of central nervous system myelin protein 2′,3′-cyclic nucleotides 3′-phosphodiesterase (CNPase) in solution of four species, and studied three proteins related to peripheral nervous system myelin: peripheral myelin protein P2, phosphoinositidi-5-phosphatase (FIG4) and SH3 domain and tetratrichopeptide repeats 2 (SH3TC2). The 3D structure of CNPase, FIG4 and SH3TC2 has not previously been solved.
In this thesis 1) the 3D structure of three P2 patient mutation proteins was solved with X-ray crystallography and the function of proteins was investigated with lipid binding assays; 2) the structure of the CNPase protein in solution was compared from four species: human (Homo sapiens), mouse (Mus musculus), orca (Orcinus orca) and green sea turtle (Chelonia mydas); and (3) various methods for purification of FIG4 and SH3TC2 proteins were screened.
Based on the research results of the thesis, it was found that patient mutations in the P2 protein (I50del, M114T and V115A) did not affect the three-dimensional structure of the protein, but decreased the heat resistance of the protein. Based on the results, it was also found that mutations M114T and V115A improved the lipid binding capacity of the protein. The solution structure of CNPase proteins was almost similar between the studied species. The purification of FIG4 and SH3TC2 proteins still requires further research. Research results can be used to understand the functioning of cells and organisms, the causes and development of diseases, and ways to intervene in them.
The axons of neurons in the central and peripheral nervous system are protected by myelin. Myelin promotes the conduction speed of the nerve impulse in the axons. Myelin proteins enable cell movement, signal transmission and immune defense. Mutations in myelin proteins cause hereditary diseases that degenerate myelin, such as leukodystrophy and types of Charcot-Marie-Tooth disease of varying severity. The spectrum of symptoms and severity of symptoms vary greatly between patients.
This dissertation compared the structure of central nervous system myelin protein 2′,3′-cyclic nucleotides 3′-phosphodiesterase (CNPase) in solution of four species, and studied three proteins related to peripheral nervous system myelin: peripheral myelin protein P2, phosphoinositidi-5-phosphatase (FIG4) and SH3 domain and tetratrichopeptide repeats 2 (SH3TC2). The 3D structure of CNPase, FIG4 and SH3TC2 has not previously been solved.
In this thesis 1) the 3D structure of three P2 patient mutation proteins was solved with X-ray crystallography and the function of proteins was investigated with lipid binding assays; 2) the structure of the CNPase protein in solution was compared from four species: human (Homo sapiens), mouse (Mus musculus), orca (Orcinus orca) and green sea turtle (Chelonia mydas); and (3) various methods for purification of FIG4 and SH3TC2 proteins were screened.
Based on the research results of the thesis, it was found that patient mutations in the P2 protein (I50del, M114T and V115A) did not affect the three-dimensional structure of the protein, but decreased the heat resistance of the protein. Based on the results, it was also found that mutations M114T and V115A improved the lipid binding capacity of the protein. The solution structure of CNPase proteins was almost similar between the studied species. The purification of FIG4 and SH3TC2 proteins still requires further research. Research results can be used to understand the functioning of cells and organisms, the causes and development of diseases, and ways to intervene in them.
Last updated: 23.1.2024