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Hi; Thesupervisor Molecular Characterizationof Components of the Nuclear Pore Complex and the Nuclear Import System in Saccharomyces cerevisiae by Jonathan David Joshua Loeb A.B., Molecular Biology University of California, Berkeley, 1987 Submitted to the Department of Biology in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biology at the Massachusetts Institute of Technology May 1995 © Jonathan D.J. Loeb 1995 All rights reserved The author hereby grants to MIT permission to reproduce and to distribute publicly copies of this thesis document in whole or in part. X 11 Signature of Author . t/ epartn t of Biology / May, 12,1995 --2 Certified.... by- I / Gerald R. Fink Professor of Biology Hi; Thesupervisor Accepted by - Frank Solomon Biology Graduate Committee Science MASSACHUSETTSINSTITUTE or rr!,l, ney JUN 06 1995 I IRRARIES Molecular Characterization of Components of the Nuclear Pore Complex and the Nuclear Import System in Saccharomyces cerevisiae by Jonathan David Joshua Loeb Submitted to the Department of Biology on May 12, 1995 in partial fulfillment of the requirements for the Degree of Doctor of Philosophy in Biology Abstract The nuclear pore complex (NPC) is the site of the bidirectional traffic of macromolecules into and out of the nucleus. Components of the NPC are responsible for regulating the active transport of macromolecules as well as organizing the structure of the nuclear envelope. This work documents the identification and characterization of two components of the NPC in the budding yeast, Saccharomyces cerevisiae that function directly in the nuclear import reaction, but also affect nuclear structure. Furthermore, I show that defects in the nuclear import of proteins lead to unexpected effects on the cell cycle, which may be evidence for a new level of regulation of mitosis. The NUP2 gene encodes a 78kD protein that belongs to a family of NPC components known as XFXFG nucleoporins. NUP2 was cloned by its cross- reactivity with an antibody raised against mammalian nucleoporins. Immunofluorescence microscopy reveals that Nup2 is located in the NPC in yeast. NUP2 is not essential, but NUP2 is required when either of the two other XFXFG nucleoporins, NSP1 or NUPI are mutated. In mammalian cells it has been shown that XFXFG nucleoporins participate in the nuclear import of proteins. NUP2 also exhibits homology to another recently identified group of soluble proteins that participate in nuclear import, known as RAN binding proteins (RanBPs). These are proteins that have been identified by their ability to bind to the small GTPase required for nuclear import, RAN/TC4. 2 SRP1 encodes the nuclear import signal sequence receptor in yeast. Mutations in this gene are unable to transport proteins into the nucleus. SRP1 mutants interact genetically with mutations in both families of nucleoporins: the XFXFG nucleoporins NUPI and NUP2 and the GLFG nucleporin NUP116. Also Srpl is in physical association with the nucleoporins Nupl and Nup2. Furthermore, a mutation in SRP1 causes conditional arrest during the cell cycle at the G2/M stage. We propose that the reason this mutant arrests is that the transport of a particular substrate for nuclear import is affected in the mutant. Candidates for the affected substrate are likely to be involved in the degradation pathway that destroys the mitotic kinase because the srpl mutant does not properly degrade the B-type cyclin Clb2. Thesis supervisor: Dr. Gerald R. Fink Title: Professor of Biology 3 For my best professors: Mom and Dad; and for my littlest professor, Elana Yosefa. 4 Acknowledgments My five years in the Fink lab have been a very valuable time. Professionally and personally I am far removed from the enthusiastic young fellow who arrived on these bleak shores, looking to learn a little science. I learned more than a little science, thanks to the MIT faculty, to Gerry Fink, and mostly to the students and post-docs with whom I shared my many days and nights in the lab. The members of the lab were very generous to me with their time, their enthusiasm and their encouragement, and I hope that I have returned these in kind. I would like to especially thank those colleagues whose help made my scientific life first possible, then enjoyable. I thank Bonnie Bartel, Per Ljungdahl, and Dave Miller for their molecular biological genius, which I exploited many times. I thank Adam Antebi, Judy Bender, Julie Brill, Chip Celenza, Paula Grisafi, Julia Kohler, Daniel Kornitzer, Nikki Levin, Hans- Ueli M6sch, Kris Niyogi, David Pellman, Cora Styles and about 50 others for their sage advice and genuine friendship. I thank Drs. Bartel, Bender and M6sch for making it cool to be tense. Furthermore, I am endebted to Patrick McCaw for his company on those 500 dinners out and to Brenda Schulman for climbing those endless hills with me. I especially thank Gabriel Schlenstedt for his help both scientific and otherwise, and for being the guy with whom I could finally talk about nuclear transport. Most importantly, I thank Tish. This saintly woman withstood years of stress and complaint with solid love, patience and understanding. I am so grateful. I will spend the next thirty years trying to make it up to you! 5 Table of contents Abstract................................................................ 2 Acknowledgments .......................................................................................................5 Table of contents ................................................................... 6 Abbreviations...................................................... 12 Chapter 1. The nuclear pore complex and nuclear transport............................ 13 1.1 The nuclear envelope ...........................................................................................14 The nuclear envelope membrane ................................................................15 Differences between organisms ....................................................................15 1.2 Nuclear transport................................................................................................... 16 The NPC is the site of transport ....................................................................17 Signals for protein import ...................................................... 20 Shuttling proteins ...................................................... 22 Nuclear export ...................................................... 23 1.3 The ultrastructure of the nuclear pore complex............................................. 25 1.4 Components of the nuclear pore complex .....................................................28 Nucleoporins...................................................... 29 Other nuclear pore proteins ...................................................... 48 Purification of nuclear pore complexes .....................................................50 1.5 Soluble factors required for nuclear import .....................................................50 Receptors for proteins targeted to the nucleus ..........................................53 The small GTPase Ran/TC4 is required for the second step of protein import...................................................... 58 Cytosolic heat shock proteins are also required for import ....................64 1.6 Genetic screens in yeast for nuclear transport mutants ................................65 RNA export mutants ...................................................... 66 1.7 Regulated nuclear import ....................................................... 67 1.8 Summary ..................................................................................................... 69 Chapter 2. Nup2, a novel yeast nucleoporin, has functional overlap with other proteins...................................................... 73 Preface .............................................................................................................................74 2.1 Introduction ...................................................... 75 2.2 Materials and Methods ...................................................... 78 Reagents...................................................... 78 6 DNA techniques ........................................................ 78 Cloning potential nucleoporin genes .......................................................78 DNA sequencing ........................................................ 81 Site-directed mutagenesis ....................................................... 81 Yeast growth conditions and strain construction .....................................82 2.3 R esults ......................................................................................................... 84 Isolation of the gene for a novel yeast nucleoporin .................................84 The 95 kilodalton protein is encoded by NUP2......................................... 85 The repeated domain defines a family of nucleoporins .........................91 Nup2 is a component of the nuclear envelope .........................................94 Strains containing a null mutation of NUP2 are viable .........................97 Nup2 function is required for viability in strains carrying truncations of Nupl ............................ .............................................. 100 Either the amino terminus of Nup2 or an amino terminal region of Nupl is required for growth ......................................................103 The amino terminus of Nup2 is also reqtired for the function of amino terminal truncations
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