Structure formation and self-organization in the early secretory pathway [Elektronische Ressource] / put forward by Jens Kühnle

Dissertationsubmitted to theCombined Faculties for the Natural Sciences and for Mathematicsof the Ruperto-Carola University of Heidelberg, Germanyfor the degree ofDoctor of Natural SciencesPut forward byDipl.Phys. Jens Kuhnleborn in Heidelberg/Doral examination:01.06.2011Structure Formation andSelf-Organizationin the Early Secretory PathwayReferees: Prof. Dr. Michael HausmannProf. Dr. Matthias Wei ZusammenfassungIm Rahmen dieser Dissertation werden di usionsgetriebene Struktur und Selb-storganisationprozesse im fruhen sekretorischen Pfad von biologischen Zellen un-tersucht. Dies umfasst Prozesse im Endoplasmatischen Retikulum (ER), demGolgi Apparat (GA) und deren Transporteinheiten. Mesoskopische Simulations-methoden werden angewandt um Phanomene auf unterschiedlichen Langenskalenzu untersuchen. Auf der Mikrometerskala werden Selbsorganisationeigenschaftendes GA untersucht und dessen erstaunliche Eigenschaft sich nach vollstandigemAbbau wieder zu regenerieren. Desweiteren besitzen unterschiedliche Organis-men eine gro e Bandbreite an GA Ph anotypen. Sowohl die dynamische Regener-ation als auch die Diversitat an Phanotypen konnen in einem einfachen Modell durch Unterschiede in der Fusions- und Transportmaschinerie erklart werden.Auf der Nanometerskala wird die Bildung von Transportvesikeln durch COPIHullenp roteine untersucht.
Publié le : samedi 1 janvier 2011
Lecture(s) : 16
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Source : D-NB.INFO/1012843947/34
Nombre de pages : 155
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Dissertation
submitted to the
Combined Faculties for the Natural Sciences and for Mathematics
of the Ruperto-Carola University of Heidelberg, Germany
for the degree of
Doctor of Natural Sciences
Put forward by
Dipl.Phys. Jens Kuhnle
born in Heidelberg/D
oral examination:
01.06.2011Structure Formation and
Self-Organization
in the Early Secretory Pathway
Referees: Prof. Dr. Michael Hausmann
Prof. Dr. Matthias Wei Zusammenfassung
Im Rahmen dieser Dissertation werden di usionsgetriebene Struktur und Selb-
storganisationprozesse im fruhen sekretorischen Pfad von biologischen Zellen un-
tersucht. Dies umfasst Prozesse im Endoplasmatischen Retikulum (ER), dem
Golgi Apparat (GA) und deren Transporteinheiten. Mesoskopische Simulations-
methoden werden angewandt um Phanomene auf unterschiedlichen Langenskalen
zu untersuchen. Auf der Mikrometerskala werden Selbsorganisationeigenschaften
des GA untersucht und dessen erstaunliche Eigenschaft sich nach vollstandigem
Abbau wieder zu regenerieren. Desweiteren besitzen unterschiedliche Organis-
men eine gro e Bandbreite an GA Ph anotypen. Sowohl die dynamische Regener-
ation als auch die Diversitat an Phanotypen konnen in einem einfachen Modell
durch Unterschiede in der Fusions- und Transportmaschinerie erklart werden.
Auf der Nanometerskala wird die Bildung von Transportvesikeln durch COPI
Hullenp roteine untersucht. Zuerst wird die von ARFGAP verursachte Ablosung
der COPI Hulle Insbesondere zeigt sich, dass eine krummungsabh ang-
ige ARFGAP-induzierte Ablosung der COPI Hulle fur die Vesikelbildung vorteil-
haft sein konnte. Anschlie end wird ein Reaktions-Di usions Modell hergelei-
tet, das sich mit der Bildung von COPI Domanen beschaftigt. Im Wesentlichen
konnen diese Domanen durch Lipid-Protein Wechselwirkungen entstehen, d.h.
bestimmte Proteine bevorzugen spezielle Lipidumgebungen und verandern gleich-
zeitig ihr Lipidmilieu.
Abstract
In this thesis di usion-driven structure formation and self-organization processes
in the early secretory pathway of living cells are studied. In particular, this
study is concerned with the endoplasmatic reticulum (ER), the Golgi apparatus
(GA), and tra c intermediates in between. Mesoscopic simulation techniques
are applied in order to study phenomena on di erent length scales. On the
micron scale self-organization properties of the (GA) and its remarkable ability
to rebuild after complete disassembly are investigated. Moreover, in di erent
organisms a wide range of GA phenotypes can be found. On the basis of the
presented model, the dynamical structure as well as various phenotypes can be
explained as a result of changes in the fusion and transport machinery. On the
nanometer level, formation of vesicles via COPI coat proteins is investigated.
First, the dissociation process of the COPI coat induced by ARFGAP is studied.
In particular, a curvature-sensitive detachment mechanism might be bene cial
for vesicle formation. Second, a reaction-di usion model is derived from existing
biological data. It is shown how COPI domains can form e ciently via lipid-
protein interactions, i.e. a preferential localization of proteins to speci c lipid
environments and a protein-mediated change of the lipid milieu.Contents
1 Introduction 9
I Prerequisites 15
2 Lipids and membranes 17
2.1 Structure of biological membranes . . . . . . . . . . . . . . . . . 17
2.2 Mathematical descriptions of membranes . . . . . . . . . . . . . 19
2.3 Lipid structure formation . . . . . . . . . . . . . . . . . . . . . 21
3 The early secretory pathway 23
3.1 The endoplasmatic reticulum . . . . . . . . . . . . . . . . . . . 23
3.2 Membrane carriers in the early secretory pathway . . . . . . . . . 25
3.3 The Golgi apparatus and its morphology . . . . . . . . . . . . . 28
4 Di usion and its role in structure formation 35
4.1 Brownian motion . . . . . . . . . . . . . . . . . . . . . . . . . . 35
4.2 Anomalous di usion . . . . . . . . . . . . . . . . . . . . . . . . 37
4.3 Measuring in biological cells . . . . . . . . . . . . . . . 39
4.4 Turing patterns as a means for cellular structure formation . . . . 40
4.5 General stability criteria . . . . . . . . . . . . . . . . . . . . . . 41
4.6 Di usion-driven instability . . . . . . . . . . . . . . . . . . . . . 43
4.7 Two-component system . . . . . . . . . . . . . . . . . . . . . . 44
II Results & Discussion 47
5 Self-organized morphogenesis of the Golgi complex 49
5.1 Model de nition . . . . . . . . . . . . . . . . . . . . . . . . . . 50
5.2 Cisternae size and amount in the protein exchange limiting case . 55
5.3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
5.4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
7CONTENTS
6 COPI Hydrolysis - a curvature mediated process? 71
6.1 Setting up the model . . . . . . . . . . . . . . . . . . . . . . . 72
6.2 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
6.3 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
7 Lipid-induced COPI clustering 81
7.1 Setting up the model . . . . . . . . . . . . . . . . . . . . . . . 82
7.2 Parameter space exploration . . . . . . . . . . . . . . . . . . . . 86
7.3 Numerical methods . . . . . . . . . . . . . . . . . . . . . . . . 88
7.4 Formation of COPI patterns . . . . . . . . . . . . . . . . . . . . 89
7.5 In uence of the cytosol . . . . . . . . . . . . . . . . . . . . . . 94
7.6 Subdi usion and Porous Media Equation . . . . . . . . . . . . . 99
7.7 Sub and pattern formation . . . . . . . . . . . . . . . . 103
7.8 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
8 Physical properties of lipid bilayers on the nanoscale 109
8.1 Dissipative Particle Dynamics . . . . . . . . . . . . . . . . . . . 110
8.2 Composition dependence of the membrane bending sti ness . . . 112
8.3 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
8.4 Are lipid membranes viscous? . . . . . . . . . . . . . . . . . . . 115
8.5 Lipid di usion characteristics . . . . . . . . . . . . . . . . . . . 117
8.6 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
9 Conclusion 123
9.1 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
9.2 Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
III Appendix 127
Bibliography 130
Acknowledgement 153
List of publications 155
8Chapter 1
Introduction
Living organisms are organized into fundamental subunits on the micron scale,
so-called cells. Biological cells can be considered as living matter as they are self-
reproducing and self-sustained entities. They feature highly complex structures
on many di erent length scales. But how does this complexity emerge? In mod-
ern cell biology it is still unclear how large cellular structures, such as organelles,
are formed and maintained. Organelles are specialized enclosed subunits within
a cell. What governs their shape and their size? Which are the responsible cues
that localize them to speci c places?
One solution to these questions is the formation of a structure due to inheritance,
i.e. via copying a template structure. Since the discovery of the deoxyribonu-
cleic acid (DNA) replication mechanism, templated inheritance has become a
widespread concept in cell biology. A drawback of this approach is that it does
not explain the origin of the template itself. A second powerful concept that
is less commonly considered in biology is self-organization. In this case, global
patterns arise from local and dynamic interactions of individual elements. The
emerging properties of the whole system are neither the product of a central au-
thority (a "mastermind"), nor can they be predicted by the individual properties
of its elements.
Does this emergence of order contradict the second law of thermodynamics?
Not necessarily, because many thermodynamic systems, e.g. biological cells,
can acquire energy from their environment, and they employ it to decrease their
entropy. Hence, they are open systems out of equilibrium. This can be illustrated
for instance in lithotrophic organisms such as bacteria or algea that harvest
sunlight. Due to ongoing chemical reactions they produce heat and thus emit
light in the infrared spectrum. By absorbing fewer photons of higher energy
and emitting more photons of lower energy they increase the entropy of their
surrounding. This enables them to create highly ordered molecular structures
from the gain in free energy.
9Figure 1.1: Schematic of a typical eukaryotic cell. The plasma membrane
separates the cellular interior from the environment. Internal membranes
separate cellular subunits so-called organelles that exert speci c functions.
The nucleus stores genetic information in form of DNA while mitochondria are
responsible for energy conversion. Other important organelles are endoplasmic
reticulum and Golgi apparatus which are both involved in cellular transport.
Image courtesy of chemistrypictures.org.

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