Summary
The shape of the fibrinogen and fibrin molecules, as shown by negative staining method as well as by sections through fibrin fibers, does not differ substantially from that of a pentagon dodekahedron. Using an electron microscopic characterization, physical data, and chemical properties of the fibrin molecule, along with the already wellknown conformation of proteins, it was possible to gain insight into the macromolecular architecture of the fibrin molecule. The architecture of the molecule corresponds to that of the pentagon dodecahedron model with a doublestranded edge. The six polypeptide chains of the fibrinogen molecule are distributed evenly along the edges of the dodecahedron in the form of a double stranded cable. Using the number of aminoacids, measurements of the molecule in the electron microscope, and reflections of x-ray diffraction studies the model permitted the construction of fictious molecules. The selection of the most probable among these fictious molecules confirmed a probable model of the fibrinogen molecule in both dehydrated and native condition.
The following facts are consistent with this probable model of the fibrinogen molecule: The model is constructible only from a superhelix of polypeptide chains and must consist of a regular alternation between α-helix and nearly stretched section of the polypeptide chains. These are both properties of proteins in general. Their existence must be assumed in order to construct the model. The length of the six polypeptide chains of the molecule in the α-helical form corresponds to about double the length of the summed edges of the model. The molecular weight as determined from the volume of the polypeptide chains shows good agreement with the molecular weight as determined from physical data about the molecule in solution. The model possesses the characteristics of a random coil as well as those of a stiff rod. The diameter and water content of the model agree with the appropriate calculations from hydrodynamic data. The flow birefringence of a fibrinogen solution can be explained by the model. The hydrodynamically effective edge lenght of the model was not calculated. The hydrodynamic properties of dissociation and degradation products of the fibrinogen molecule are consistent with the model. The agreement between the model and calculations of the proportion of α-helix in the fibrinogen molecule as measured by optical rotatory dispersion is not satisfying. The detailed structure of the edges and corners of the model and the question of whether the ends of the polypeptide chains fit into the architecture of edges or corners or whether they stick out from the skeleton of the molecule remains unknown.
Fibrin fibers show two groups of periodic structures in electron microsocpic sections, with intervals of 200–208 Å for the larger period and 165–170 Å for the smaller period, which occur either transversally or at definite angles to the axis of the fiber. These periodic structures are caused by polypeptide chain cables which project over one another in the periphery of the molecular structure. The variation in the periodic intervals can be explained by the various diameters of the dodecahedron, while the angles result from the direction taken by the polypeptide chain cables in the projection. The intermolecular gaps in the fibrin fibers produce the most substantial contrast in the cross-striations along the fibers; the reason for this contrast is not known. The non-periodic structures of the fibrin fibers are generated from the polypeptide chain cables which project into the inside of the molecular structure. In lengthwise sectioned planes of fibrin fibers prepared at pH 6,35 the diameter between two edges of each fibrin molecule is parallel to the fiber axis while the diameter between two faces is perpendicular to the fiber axis. A definite three-dimensional explanation for the fiber structure is not yet possible.
Masking and demasking of active groups on side chains may be explained by rotation of the polypeptide chains and/or the polypeptide chain cables in the region of the edges. Useful there is a regular alternation between helix-formed polypeptide chain regions along the edges and stretched out polypeptide chain sections running in the region of the corners of the model; this may suffice to incorporate only one amino acid from the α-helix of a chain in the stretched out polypeptide chain chain section running along each corner.
It is to be expected that the structure demonstrated for the fibrinogen and fibrin molecule may also be realized, at least at similar form, among a number of other macromolecules. Linear aggregates, zig-zag aggregates, and helical aggregates of various lengths, as well as membrane-like and crystalloide formations can be constructed from the basic dodecahedron form. The length of the aggregates is dependent on the positions of the various axes of the dodekahedron. Shortening and lengthening of the aggregate can be produced by tipping over the molecules. This tipping over mechanism is interesting as a possibility for the explanation of motion processes within cells and of cells: locally fixed chemical energy of the polypeptide chains could be transformed into motion by this mechanism. In addition, dodecahedrons may be used in the construction of membrane-like and crystalline formations. Macromolecules in the form of a polyhedron-edged model may represent storage structures.
Zusammenfassung
Sowohl nach negativer Kontrastierung, als auch in Schnitten durch Fibrinfasern weicht die Gestalt des Fibrinogen- und Fibrinmoleküls im Elektronenmikroskop nicht wesentlich von der Gestalt eines Pentagondodekaeders ab. Mit Hilfe elektronenmikroskopischer Charakteristica, physikalischer Daten und chemischer Eigenschaften des Fibrinogenmoleküls und mit Hilfe der bisher bekannt gewordenen Konformation der Proteine war es möglich, in den makromolekularen Bau des Fibrinogenmoleküls Einblick zu erhalten. Der Bau des Moleküls entpsricht weitgehend dem des Pentagondodekaeder-Zweistrang-Kantenmodells: Die 6 Polypeptidketten des Fibrinogenmoleküls verteilen sich in Form von Zweistrangkabeln gleichmäßig über die Kanten der Dodekaederform. Das Modell erlaubt es, aus der Zahl der Aminosäuren, aus den Abmessungen des Moleküls im Elektronenmikroskop und auf Grund eines Röntgenbeugungsreflexes Fiktivmoleküle zu konstruieren. Mit Hilfe der Fiktivmoleküle wurde das Modell eines wahrscheinlichen Fibrinogenmoleküls im dehydratisierten und im nativen Zustand erhalten.
Für das wahrscheinliche Modell des Fibrinogenmoleküls sprechen: Das Modell ist nur mit Hilfe einer Superhelix der Polypeptidketten konstruierbar, und es erfordert einen regelmäßigen Wechsel zwischen α-Helixabschnitten und gestreckten Abschnitten der Polypeptidketten. Beides sind Eigenschaften, die für Proteine nachgewiesen sind. Ihre Existenz ist eine Voraussetzung für die Konstruierbarkeit des Modells. Die Länge der 6 Polypeptidketten des Moleküls in α-Helixform entspricht nahezu der doppelten Länge sämtlicher Kanten des Modells. Das Molekulargewicht aus dem Volumen der Polypeptidketten zeigt gute Übereinstimmung mit dem Molekulargewicht aus physikalischen Daten des Moküls der Lösung. Das Modell vereinigt die Eigenschaften eines statistischen Knäuels mit den Eigenschaften starrer Stäbchen. Durchmesser und Wassergehalt des Modells stimmen mit entsprechenden Berechnungen aus hydrodynamischen Daten überein. Die Strömungsdoppelberechnung von Fibrinogenlösungen ist anhand des Modells erklärbar. Die hydrodynamisch wirksame Kantenlänge des Modells wurde nicht abgeschätzt.
Die hydrodynamischen Eigenschaften von Dissoziations- und Abbauprodukten des Fibrinogenmoleküls sind mit Hilfe des Fibrinogenmodells erklärbar. Die Übereinstimmung zwischen dem Modell und den Berechnungen des α-Helixanteils des Fibrinogens auf Grund der optischen Rotationsdispersion ist nicht befriedigend. Im Modell bleiben unbekannt: Die detaillierte Struktur der Kanten und Ecken und die Frage, ob die Enden der Polypeptidketten am Aufbau von Kanten oder von Ecken des Moleküls beteiligt sind oder ob sie aus dem Umriß des Moleküls herausragen.
Fibrinfasern zeigen im elektronenmikroskopischen Schnitt zwei Gruppen periodischer Strukturen mit Abständen von 200 bis 208 Å und 165 bis 170 Å, die quer oder in bestimmten Winkeln zur Faserachse verlaufen können. Diese periodischen Strukturen sind verursacht durch Polypeptidkettenkabel, die in der Peripherie des Molekülbildes übereinander projiziert werden. Die verschiedenen Periodenabstände erklären sich aus den verschiedenen Durchmessern der Dodekaederform, die Winkel aus der Verlaufsrichtung der Polypeptidkettenkabel in der Projektion. Die intermolekularen Lücken in den Fibrinfasern liefern den bedeutendsten Kontrastanteil der Querstreifung der Fasern; die Ursache des Kontrastes ist nicht bekannt. Die nicht-periodischen Strukturen der Fibrinfasern sind von Polypeptidketten-Kabeln hervorgerufen, die in das Innere des Molekülbildes projiziert werden. In Fibrinfasern, die bei pH 6,35 entstanden sind, liegen die Fibrinmoleküle in einer Längsschnittebene mit einem Durchmesser zwischen 2 Kanten parallel und mit einem Durchmesser zwischen 2 Flächen quer zur Faserachse; die räumliche Aufklärung der Faserstruktur steht noch aus.
Ein regelmäßiger Wechsel zwischen helixförmigen Polypeptidkettenabschnitten entlang von Kanten und gestreckt verlaufenden Polypeptidkettenabschnitten im Bereich von Ecken des Modells erlaubt es, die Maskierung und Demaskierung von aktiven Gruppen an Seitenketten durch Drehung der Polypeptidketten und/oder der Polypeptidkettenkabel im Bereich der Kanten zu erklären; dabei dürfte es genügen, daß nur eine Aminosäure aus der α-Helix einer Kante in den gestreckt verlaufenden Polypeptidketten-Abschnitt einer Ecke einbezogen wird.
Es ist zu erwarten, daß die am Fibrinogen- und Fibrinmolekül nachgewiesene Struktur zumindest in ähnlicher Form auch bei einer Reihe anderer Makromoleküle realisiert ist. Aus Dodekaederformen können Linearaggregate, Zick-Zack-Aggregate und Helixaggregate verschiedener Länge sowie membranähnliche und kristallähnliche Gebilde konstruiert werden. Die Länge dieser Aggregate ist abhängig von der Lage der verschieden langen Achsen der Dodekaederform. Durch Umklappen der Moleküle können Verkürzungen und Verlängerungen der Aggregate hervorgerufen werden. Dieser Umklappmechanismus ist als Möglichkeit für die Erklärung von Bewegungsvorgängen in und von Zellen interessant: Es wird lokal fixierte chemische Energie der Polypeptidketten in Bewegung verwandelt. Außerdem erlaubt die Dodekaederform die Konstruktion von membranähnlichen und kristallähnlichen Gebilden. Makromoleküle in Form von Polyeder-Kantenmodellen können Speicherstrukturen darstellen.
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Die Arbeit hat in ungekürzter Form der Medizinischen Fakultät der Justus Liebig-Universität Gießen als Habilitationsschrift vorgelegen.
Im Auszug vorgetragen auf der Tagg. Dtsch. u. Niederländ. Ges. Elektronenmikroskopie, Aachen, 31. Okt.–2. Nov. 1965, 10. Tagg. Dtsch. Arbeitsgemeinschaft Blutgerinnungsforsch., Würzburg, 27.–30. März 1966.
Die Arbeit konnte dank der Hilfe der Deutschen Forschungsgemeinschaft durchgeführt werden.
Für technische Assistenz danke ich Frau I. Wagner, Herrn M. Hesse und Herrn H. Nolte.
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Köppel, G. Elektronenmikroskopische Untersuchungen zur Gestalt und zum makromolekularen Bau des Fibrinogenmoleküls und der Fibrinfasern. Z. Zellforsch. 77, 443–517 (1967). https://doi.org/10.1007/BF00319345
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DOI: https://doi.org/10.1007/BF00319345