Medical Biology and Genetics Lecture Notes 2024 PDF

KOCAELİ HEALTH AND TECHNOLOGY UNIVERSITY FACULTY OF PHARMACY (ENGLISH) MEDICAL BIOLOGY and GENETICS Lecture-3 Organelles Assist. Prof. Dr. Seval ÇINAR [email protected] 2024 Nucleus The nucle...

KOCAELİ HEALTH AND TECHNOLOGY UNIVERSITY FACULTY OF PHARMACY (ENGLISH) MEDICAL BIOLOGY and GENETICS Lecture-3 Organelles Assist. Prof. Dr. Seval ÇINAR [email protected] 2024 Nucleus The nuclear envelope is a double membrane structure that encloses the nucleus in eukaryotic cells, separating the nucleoplasm from the cytoplasm. The nuclear envelope comprises two lipid bilayers: the inner nuclear membrane and the outer nuclear membrane, which is continuous with the endoplasmic reticulum. Nuclear pores that facilitate the transport of proteins and RNA molecules.  Nuclear Envelope-Related Disorders: Disorders associated with defects in the nuclear envelope can result in a range of diseases, often referred to as nuclear envelope disorders or laminopathies. Many of these disorders are linked to mutations in the genes encoding nuclear envelope proteins, particularly lamin A/C, which are key elements of the nuclear lamina. Some notable disorders include: →Muscular Dystrophy: Inherited genetic disorders characterized by progressive weakness and degeneration of the skeletal muscles These disorders primarily occur due to mutations in the genes responsible for maintaining healthy muscle fibers. Certain forms of muscular dystrophy, such as Emery-Dreifuss muscular dystrophy, are associated with mutations in the emerin (a nuclear envelope protein). This leads to muscle wasting and joint contractures.  Nuclear Envelope-Related Disorders: →Progeria (Hutchinson-Gilford Progeria Syndrome): Progeria Syndrome is a rare genetic disorder characterized by rapid aging in children. Caused by a mutation in the LMNA gene that produces a defective form of lamin A called progerin. This leads to premature aging features, cardiovascular problems, and reduced life expectancy. LMNA gene encodes lamin A and lamin C Ribosomes They are found in all cells They are not membranous. Ribosomes are the sites of protein synthesis in both prokaryotic and eukaryotic cells. Both prokaryotic and eukaryotic ribosomes consist of large and small subunits, which contain both ribosomal proteins and rRNAs. Their basic structure is the RNA-protein complex (ribonucleoprotein) → Location in the Cell: Free Ribosomes: These float freely in the cytoplasm and typically synthesize proteins that function within the cytosol. Bound Ribosomes: These are attached to the endoplasmic reticulum (ER), forming rough ER, and are involved in synthesizing proteins that are either secreted from the cell or incorporated into cellular membranes.  Ribosomes Intact prokaryotic and eukaryotic ribosomes are designated 70S and 80S, respectively, on the basis of their sedimentation rates in ultracentrifugation. S: Svedberg unit=Sedimentation coefficient In eukaryotes, the large subunit is known as 60S, and the small subunit is 40S, combining to form an 80S ribosome. In prokaryotes, the subunits are 50S (large) and 30S (small), forming a 70S ribosome. The small subunit is primarily responsible for reading the mRNA (messenger RNA) The large subunit is where peptide bonds are formed between amino acids to create proteins. Cytoplasm: The gel-like substance within the cell membrane that contains organelles, where various cellular processes occur. Cytoplasm: It is the name given to all the contents of the cell. Cytoplasm contains cytosol, organelles (in eukaryotes), ribosomes, nutrient granules, metabolites and ions. Cytosol: The fluid that fills the cytoplasm.  The Plasma Membrane All cells—both prokaryotic and eukaryotic—are surrounded by a plasma membrane (cell membrane) Separates and protects the interior of all cells from the external environment. It plays a critical role in maintaining the cell's integrity and homeostasis. Structure of the Eukaryotic Plasma Membrane 1.Phospholipid bilayer: 1. Hydrophilic heads face outward 2. Hydrophobic tails face inward Amphipathic (Amphiphilic) Molecule: It is a molecule that has both hydrophilic and hydrophobic parts in its structure. Phospholipids are amphipathic 2. Membrane proteins: 1. Integral proteins: span the entire membrane 2. Peripheral proteins: attached to one side 3. Cholesterol: provides stability and fluidity 4. Glycoproteins and glycolipids: carbohydrate chains on the outer surface  The membranes of animal cells contain five major phospholipids: phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin Phospholipids are asymmetrically The outer leaflet consists predominantly of phosphatidylcholine, sphingomyelin, and glycolipids Organization of plasma membrane lipids The inner leaflet contains phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. Cholesterol is distributed in both leaflets. The Fluid Mosaic Model Proposed by Singer and Nicolson in 1972 Describes the plasma membrane as a fluid structure with freely moving components Key features: Phospholipids can move laterally within the membrane Proteins can diffuse within the lipid bilayer Asymmetrical distribution of lipids and proteins Membrane fluidity affected by temperature and cholesterol content Functions of the Eukaryotic Plasma Membrane 1.Selective permeability: 1. Controls movement of substances in and out of the cell 2. Acts as a selective barrier between cell and environment 3. Allows passage of small, nonpolar molecules 4. Regulates movement of larger or charged molecules 2.Cell recognition: 1. Glycoproteins and glycolipids on the outer surface 2. Glycoproteins act as cellular ‘ID tags’ 3. Important for immune system function and cell-cell communication 3.Signal transduction: 1. Membrane proteins can act as receptors for hormones and other signaling molecules and detect external signals 2. Triggers intracellular responses 4.Enzymatic activity: 1. Some membrane proteins function as enzymes  Membrane Transport Mechanisms The passage of most biological molecules is mediated by carrier or channel proteins that allow polar and charged molecules to cross the plasma membrane without interacting with its hydrophobic interior. 1.Passive transport: 1. Diffusion: movement of molecules from high to low concentration 2. Facilitated diffusion: assisted by channel or carrier proteins 2.Active transport: 1. Requires energy (ATP) 2. Pumps molecules against their concentration gradient 3.Bulk transport: 1. Endocytosis: brings materials into the cell 2. Exocytosis: releases materials from the cell 1. Passive Transport It does not require energy (ATP) It occurs along the concentration gradient, meaning substances move from an area of higher concentration to an area of lower concentration. Simple Diffusion: The movement of small, nonpolar molecules (like oxygen and carbon dioxide) directly through the lipid bilayer. Facilitated Diffusion: This involves specific transport proteins that help larger or polar molecules (like glucose and ions) pass through the membrane. Examples include: Carrier Proteins: Bind to specific molecules and change shape to shuttle them across the membrane. Channel Proteins: Form pores that allow specific ions or water to pass through. Osmosis: The diffusion of water across a semipermeable membrane. Water can move through the lipid bilayer but more commonly passes through specialized channels called aquaporins 2. Active Transport Movement of molecules against concentration gradient Requires energy input (usually ATP) Moves substances from areas of lower to higher concentration Essential for maintaining cellular homeostasis Mechanisms of Active Transport 1.Primary Active Transport: Directly uses ATP for energy Example: Na⁺/K⁺-ATPase pump 2.Secondary Active Transport: Uses electrochemical gradient created by primary active transport Examples: glucose and amino acid transport 3. Bulk Transport (Vesicular Transport) This mechanism is used for transporting large molecules or particles that cannot fit through the membrane. It requires energy and involves the creation of vesicles. Endocytosis: The process of bringing substances into the cell. Phagocytosis: "Cell eating" - engulfing large particles or cells. Pinocytosis: "Cell drinking" - taking in fluids and small solutes. Exocytosis: The process of expelling materials from the cell by vesicles that fuse with the plasma membrane, releasing their contents outside. Phagocytosis Binding of a bacterium to the cell surface stimulates the extension of a pseudopodium, which eventually engulfs the bacterium. Fusion of the pseudopodium membranes then results in formation of a large intracellular vesicle (a phagosome). The phagosome fuses with lysosomes to form a phagolysosome within which the ingested bacterium is digested.  4. Specialized Transport Mechanisms Aquaporins: Water channels that facilitate rapid water movement across the membrane. Ion Channels: Specialized proteins that allow specific ions to pass through the membrane, typically responding to stimuli (voltage- gated, ligand-gated, or mechanically gated).  Protein Sorting and Transport The Endoplasmic Reticulum, Golgi Apparatus, and Lysosomes The endoplasmic reticulum (ER): Eukaryotic cells have a variety of membrane-enclosed organelles within their cytoplasm, in addition to nucleus. ER is a network of membrane-enclosed tubules and flattened sacs that extends from the nuclear membrane throughout the cytoplasm. There are two membrane domains within the ER that perform different functions within the cell: The rough ER,which is covered by ribosomes on its outer (cytosolic) surface Protein synthesis and modification Produces proteins for secretion or insertion into cell membranes The smooth ER is not associated with ribosomes. Main functions: Lipid synthesis Carbohydrate metabolism Detoxification of drugs and harmful substances The ER and Cellular Transport ER works closely with the Golgi apparatus Vesicles bud off from the ER, carrying proteins and lipids These vesicles fuse with the Golgi for further processing Some proteins are sent directly to their destinations from the ER The ER's role in protein targeting: Signal Recognition Particle (SRP): Recognizes signal sequences Translocation: Movement of proteins into the ER lumen Post-translational modifications in the ER: 1.Folding 2.Glycosylation 3.Disulfide bond formation  Protein Sorting Proteins synthesized on free ribosomes either remain in the cytosol or are transported to the nucleus, mitochondria, chloroplasts, or peroxisomes. In contrast, proteins synthesized on membrane-bound ribosomes are translocated directly into the ER through the translocon. These proteins contain signal sequences (indicated in red) that are cleaved during translocation. Proteins that are translocated into the ER may be either retained within the ER or transported to nuclear membranes, peroxisomal membranes, or the Golgi apparatus and, from there, to endosomes, lysosomes, the plasma membrane, or the cell exterior via secretory vesicles.  Protein targeting to the endoplasmic reticulum (ER) is a crucial process in cellular biology that ensures proteins are correctly localized within the cell. 1. Signal Peptide: ER-bound proteins usually have an N-terminal signal peptide that is recognized by the signal recognition particle (SRP) during translation. 2. Translation and SRP: As a protein is targeting of secretory proteins to the ER synthesized, the signal peptide emerges, prompting SRP to bind and direct the complex to the ER membrane, pausing translation. 3. Translocon: The ribosome binds to the ER membrane via the translocon, allowing the polypeptide to enter the ER lumen or membrane. 4. Co-Translational Translocation: Translation resumes as the polypeptide chain is threaded into the ER. 5. Protein Folding and Modifications: In the ER, proteins fold with the help of chaperones and undergo modifications like glycosylation. 6. Quality Control: The ER ensures only correctly folded proteins move along the secretory pathway. Misfolded proteins are targeted for degradation. 7. Transport to Golgi Apparatus: Correctly folded proteins are packaged into vesicles and sent to the Golgi for further processing. Endoplasmic Reticulum (ER) Stress and Related Disorders: ER stress occurs when misfolded proteins accumulate Under normal conditions, the ER maintains cellular homeostasis; however, various stressors—such as oxidative stress, inflammation—can lead to ER stress. Since only correctly folded proteins are transported to the Golgi apparatus, unfolded proteins accumulate in ER and cause ER stress. Endoplasmic Reticulum (ER) Stress and Related Disorders: This stress triggers a cellular response known as the unfolded protein response (UPR). UPR aims to restore normal ER function by: Increasing protein folding capacity Decreasing protein synthesis Increasing degradation of misfolded proteins Prolonged or unresolved ER stress can lead to cell dysfunction and death, contributing to various diseases. Endoplasmic Reticulum (ER) Stress and Related Disorders: ER dysfunction linked to various diseases: 1.Neurodegenerative Diseases: Alzheimer's Disease: Complex neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and behavioral changes. Certain genes increase the risk of developing Alzheimer's. The presence of the ‘apolipoprotein E’ allele is a significant genetic risk factor One area of research that has also gained attention in recent years is the role of endoplasmic reticulum (ER) stress in Alzheimer's disease. Emerging evidence indicates that ER stress contributes to the development of AD. In AD, protein aggregation (such as, amyloid-beta and tau) can overwhelm the protein folding capacity of the ER, leading to ER stress and neuronal death. Endoplasmic Reticulum (ER) Stress and Related Disorders: ER dysfunction linked to various diseases: 2. Metabolic Disorders: Insulin Resistance: ER stress has been implicated in the development of insulin resistance, a hallmark of type 2 diabetes. When the ER is stressed, it can lead to inflammation and impaired insulin signaling pathways, contributing to metabolic dysfunction. Obesity: ER stress in adipocytes (fat cells) can lead to altered lipid metabolism and inflammation, promoting the development of obesity-related metabolic disorders. Golgi apparatus The Golgi apparatus, also known as the Golgi complex. Often described as the cell's "shipping and packaging center" Plays a vital role in modifying, sorting, and packaging proteins and lipids for distribution Structure of the Golgi Apparatus Composed of a series of flattened, membrane-bound sacs called cisternae Typically arranged in a stack of 5-8 cisternae Two distinct faces: cis face: Receives vesicles from the endoplasmic reticulum trans face: Sends modified molecules to their final destinations Associated with numerous small vesicles for transport Golgi apparatus Importance in Cell Function Essential for proper protein and lipid modification Crucial for cellular secretion processes Vital for the formation of the cell wall in plant cells Congenital Disorders of Plays a role in cell division by helping to form the cell plate Glycosylation Disorders related to Golgi dysfunction can lead to various diseases, including Congenital Disorders of Glycosylation (CDG) →CDGs are a group of inherited metabolic disorders caused by defects in the glycosylation process, which often involves the Golgi apparatus. These disorders can lead to a range of symptoms, including developmental delays, intellectual disability, and multiorgan dysfunction. Lysosomes Lysosomes are membrane-bound organelles found in eukaryotic cells that contain enzymes necessary for breaking down various biomolecules. They play a crucial role in the cell's waste disposal system by digesting macromolecules, old cell parts, and microorganisms. Here are some key features and functions of lysosomes: Structure: Membrane-bound: Lysosomes are surrounded by a single lipid bilayer that protects the rest of the cell from the enzymes contained within. Enzymes: They contain hydrolytic enzymes, including proteases, lipases, and nucleases, which are active at the acidic pH maintained inside the lysosome. Functions of lysosomes: 1.Digestion: They break down complex molecules (proteins, lipids, carbohydrates, and nucleic acids) into simpler ones that can be reused by the cell. 2.Autophagy: Lysosomes play a significant role in autophagy, the process where cells degrade and recycle their own components, including damaged organelles. 3.Defense: They can destroy pathogens that have been engulfed by the cell, such as bacteria and viruses. Autophagy 4.Cell signaling: Lysosomes also participate in Regions of the cytoplasm or internal organelles (such as cellular signaling pathways and can influence mitochondria) are enclosed by membranes derived from the endoplasmic reticulum, forming autophagosomes. metabolic processes. Autophagosomes fuse with lysosomes to form large phagolysosomes in which their contents are digested. Associated Diseases: Lysosomal storage disorders: Inability to break down certain molecules. These conditions are caused by genetic defects that affect the enzymes responsible for processing substrates within the lysosome. Result: accumulation of harmful substances in cells Examples: Gaucher disease, Tay-Sachs disease →Gaucher disease is the most common lysosomal storage disease and but is quite rare. Mutations in the GBA gene, which is responsible for the production of enzymes that break down lipids, cause this condition. →Tay Sachs disease, a rare genetic disorder, deeply affects the nervous system, especially in infancy.  Topology of the secretory pathway The lumens of the ER and Golgi apparatus are topologically equivalent to the exterior of the cell. Consequently, those portions of polypeptide chains that are translocated into the ER are exposed on the cell surface following transport to the plasma membrane.