Volltextdatei(en) vorhanden
Titel: Structural investigation and characterisation of the sarcomeric Z-Disk Titin-Obscurin-Complex and the M-Band Myomesin My5-Dimer
Sonstige Titel: Strukturuntersuchung und Charakterisierung des sarkomerischen Z-Scheiben Titin-Obscurin-Komplexes und des M-Banden Myomesin My5-Dimers
Sprache: Englisch
Autor*in: Hornburg, Philipp
Schlagwörter: Obscurin; Z-Scheibe; M-Bande; Proteinkristallographie; Z-Disk; M-Band
GND-Schlagwörter: Titin; Muskelproteine; Myomesin; Sarkomer; Muskelkrankheit; SNP
Erscheinungsdatum: 2018
Tag der mündlichen Prüfung: 2020-01-23
Zusammenfassung: 
The fundamental functions of muscles are enabling flexibility and dynamics on the one hand while providing stability on the other. This contradictory principle of motion and rigidity needs to be finely regulated and thus requires highly ordered sub-cellular structures. An essential part in these processes play the three muscle proteins titin, obscurin and myomesin. Through targeted protein-protein interactions, titin guides numerous proteins to their specific spatial positions within the sarcomere, thus ensuring the controlled assembly of the muscle structure. Titin interacts with obscurin on both the M-band and the Z-disk, two positions more than 1 μm apart. While the interaction at the M band has already been structurally described and functionally investigated, little is known about the interaction at the Z-disk involving the titin domains Z8 and Z9 and the obscurin domains O58 and O59. In addition to titin and obscurin, myomesin is another structural protein responsible for the anchoring of the myosin filament in the M band. A crystal structure has shown that the fifth domain of myomesin may have a special type of dimerization that could further increase the structural stability of myomesin anchoring.
The work presented here, therefore, addresses i) the yet unsolved molecular structure of the titin-obscurin complex at the Z-disk and ii) the characterization of the dimerization of the My5 domain.
By solving the high-resolution X-ray crystal structure of the titin-obscurin complex and using complementary biophysical methods such as size exclusion chromatography, isothermal titration calorimetry, or small-angle X-ray scattering, it was, for the first time, possible to present a comprehensive model of the Z-disk interaction between titin and obscurin. Including extensive database analysis of single nucleotide polymorphisms within these structures and the interpretation of their impact on the molecular structure of the complex, attractive hypotheses for the involvement of four instead of two domains in complex formation have been proposed and the first model for the complete regulatory mechanism of the complex was developed.
In the second part of the thesis, the mechanism of My5 domain dimerization is structurally analysed and shown to be of physiological importance as well as central for the stability of the sarcomere. In addition, this work presents a composite model combining all available high-resolution structures of myomesin, representing the most complete structural model of myomesin to date and further supporting the proposed myomesin M-band assembly.
In summary, this dissertation demonstrates in two different systems that the structural information plays an important role to understand the nature and behaviour of proteins and their regulatory mechanisms. However, only by considering the native environment and in combination with other methods, it will be possible to draw valid conclusions about the molecules behaviour in a broader context.
URL: https://ediss.sub.uni-hamburg.de/handle/ediss/6260
URN: urn:nbn:de:gbv:18-104205
Dokumenttyp: Dissertation
Betreuer*in: Schneppenheim, Reinhard (Prof. Dr.)
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen

Dateien zu dieser Ressource:
Datei Beschreibung GrößeFormat  
Dissertation.pdf9.13 MBAdobe PDFÖffnen/Anzeigen
Zur Langanzeige

Diese Publikation steht in elektronischer Form im Internet bereit und kann gelesen werden. Über den freien Zugang hinaus wurden durch die Urheberin / den Urheber keine weiteren Rechte eingeräumt. Nutzungshandlungen (wie zum Beispiel der Download, das Bearbeiten, das Weiterverbreiten) sind daher nur im Rahmen der gesetzlichen Erlaubnisse des Urheberrechtsgesetzes (UrhG) erlaubt. Dies gilt für die Publikation sowie für ihre einzelnen Bestandteile, soweit nichts Anderes ausgewiesen ist.

Info

Seitenansichten

24
Letzte Woche
Letzten Monat
geprüft am 13.04.2021

Download(s)

27
Letzte Woche
Letzten Monat
geprüft am 13.04.2021
Werkzeuge

Google ScholarTM

Prüfe