07. Module 7.pdf

MODULE 7 Introduction Nucleus: Acts as the 'control center,' storing hereditary information (DNA) and responsible for RNA and ribosome production. Nuclear Envelope: Consists of two membranes with nuclear pore complexes (NPCs). - Inner membrane: Contains proteins that bind to chromatin and the...

MODULE 7 Introduction Nucleus: Acts as the 'control center,' storing hereditary information (DNA) and responsible for RNA and ribosome production. Nuclear Envelope: Consists of two membranes with nuclear pore complexes (NPCs). - Inner membrane: Contains proteins that bind to chromatin and the nuclear lamina. - Outer membrane: Continuous with the endoplasmic reticulum (ER) and covered in ribosomes. Nuclear Lamina: Meshwork of intermediate filaments (lamins) that provide structural support. Nucleolus: Comprises 25% of the nuclear volume, essential for rRNA transcription and ribosomal assembly. Functions of the Nuclear Envelope Controls macromolecular trafficking between the nucleus and cytosol. Anchors chromosomes. Provides continuity with the rough ER. Offers genetic protection and regulation. Nuclear Lamins Structure: Intermediate filament proteins containing nuclear localization signals (NLS). Two types, A- and B-type lamins. - A-type lamins: Encoded by the LMNA gene, spliced into isoforms lamin A and lamin C. - Some lamins exist as prelamins that undergo post-translational modifications. Functions: - Mechanical support for proteins. - Chromatin organization via interactions with DNA and histones. - Gene regulation during differentiation. - DNA repair and genome stability maintenance. Lamin Mutations and Degenerative Disorders 1. Hutchinson-Gilford Progeria Syndrome (HGPS): - Caused by a mutation in the LMNA gene, producing the lamin A variant, progerin. - Progerin remains attached to the inner nuclear membrane, leading to accelerated aging and death from cardiovascular diseases in teenage years. 2. Emery-Dreifuss Muscular Dystrophy (EDMD): - Caused by mutations in LMNA and other genes. - Affects skeletal and cardiac muscles, leading to joint deformities and heart problems (e.g., bradycardia, heart failure). MODULE 7 Nuclear Pore Complexes (NPCs) and Transport Signals Structure and Function: The nuclear envelope has approximately 4,000 NPCs for the passive diffusion of molecules under 40 kD and facilitated transport of larger molecules. NPCs: Protein channels (nucleoporins) that regulate bidirectional gated transport. Larger molecules require a nuclear localization signal (NLS) for import or a nuclear export signal (NES) for export, facilitated by importins and exportins (receptors). FG-repeats: Repeats of phenylalanine and glycine form a mesh-like barrier, but transport receptors bind and traverse this barrier to enable movement. Ran GTPase Drives Nuclear Transport Transport of molecules larger than 40 kD requires GTP hydrolysis and importin/exportin (karyopherins) receptors. Ran GTPase Cycle: - Import: Importin binds NLS cargo → enters the nucleus → Ran-GTP releases cargo → Ran-GTP-importin exits to the cytoplasm → Ran-GAP hydrolyzes GTP to GDP → importin is released. - Export: Ran-GTP binds exportin and NES cargo → exits to the cytoplasm → Ran-GAP hydrolyzes GTP to GDP → exportin and cargo dissociate. RNA Transport Proteins binding to mRNAs contain nuclear localization/export signals. RNA Export: mRNAs bind to shuttling proteins during transcription and splicing. Incompletely processed mRNAs remain in the nucleus until fully processed. Disassembly and Assembly of the Nuclear Envelope Mitosis: The nuclear lamina depolymerizes due to the phosphorylation of lamins, and NPCs disassemble. Reassembly: In late mitosis, ER membranes surround and fuse around chromosomes, reforming the nuclear envelope. Nuclear localization signals remain intact, allowing repeated nuclear importation. Summary The nucleus, enclosed by a double membrane, contains genomic DNA and the nucleolus for ribosome production. The nuclear envelope consists of inner and outer membranes, with the outer membrane continuous with the rough ER. RNAs and ribosomal subunits with export signals are transported to the cytoplasm, while proteins with nuclear localization signals are synthesized in the cytosol and imported into the nucleus. Traffic between the nucleus and cytosol is regulated through NPCs, with GTPase Ran providing directionality for transport. Nuclear localization/export signals are retained, enabling proteins to shuttle repeatedly.