BAR Dmains, Types, Mechanism, Functions.pptx

This ppt inlcudes BAR domain , introduction, Types and Functions.

1. BAR Domain Muhammad Mujtaba Steve John Muhammad Abdullah Muhammad Waqar

2. Contents: Domain BAR Domain Structure Types of BAR Domain Binding Mechanism Functions Any diseases related Future directions

3. Domain A region of protein Stable structure Perform a specific function Independent of rest of proteins Examples Kinase Domain Immunoglobulin (Ig) Domain Kinase Domain Immunoglobulin (Ig) Domain

4. BAR DOMAIN:   The BAR (Bin/ Amphiphysin / Rvs ) domain found in certain proteins that play a role in membrane dynamics and cellular processes. Named after the proteins in which they were first identified: Bin, Amphiphysin , Rvs . Crescent-Shaped Structure or banana like structure (peter et al.,2004)

5. Structure : Consist of two dimers, contain 3 α-helices each ( Stanishneva-konovaolva et al., 2016). Positively Charged concave Surface (charge residue lysines and arginines ) Held together by non-covalent interactions ( H-bonding , Hydrophobic interaction Electrostatic interaction)

6. Types of BAR domain N BAR Crescent-shaped Contains an N-terminal amphipathic helix induces inward sharp curvature interact through concave surface Examples Drosophila, Amphiphysin N BAR.

7. F BAR More elongated and less sharply curved structure  Generate membranes with more gentle curvatures, Generates inward curvature Interact through concave surface Examples Muniscin , syndapins

8. I BAR Inverse to N BAR domain convex structure Generate outward curvature Interact through convex surface Examples Endophilin Protein

9. Comparative structures of N, I, F BAR Domain

10. Structure of BAR Domain Dimeric, Crescent Shape: The BAR domain forms a banana-shaped dimer, with two protein subunits creating a coiled-coil structure. Membrane Curvature: Its curved, positively charged surface interacts with negatively charged lipid membranes, inducing or stabilizing membrane curvature. Amphipathic Helices (N-BAR): Some BAR domains contain amphipathic helices that insert into the membrane, promoting curvature. Variants: N-BAR: Additional helix for stronger membrane binding. F-BAR: Generates gentler curvature for broader membrane protrusions. I-BAR: Involved in forming concave membrane invaginations.

11. Binding Mechanism Electrostatic Interactions: The concave face of the BAR domain is rich in positively charged amino acids (lysine and arginine) interact with the negatively charged lipid head groups present in the cellular membrane (phosphatidylserine and phosphoinositides ) This electrostatic interaction is essential for initial membrane attachment, ensuring the BAR domain docks onto the membrane surface. Shape Complementarity: The BAR domain's crescent or banana-like shape is key to its function in membrane binding. This shape is complementary to the curvature of membranes, especially those that are convex (outwardly curved), such as small vesicles or highly curved membrane regions. When the BAR domain binds, it either: Induces curvature in a relatively flat membrane by stabilizing a bend. Senses and stabilizes existing curvature, helping the cell maintain or further deform a curved membrane

12. Amphipathic Helices Insertion (N-BAR Domains): In N-BAR domains (a subtype of BAR domains), additional amphipathic helices at the N-terminus insert directly into the membrane’s hydrophobic core. These helices wedge themselves between the lipid molecules, further destabilizing the lipid bilayer and promoting additional membrane bending or curvature. This insertion creates a stronger and more localized effect on the membrane curvature, which is particularly important in processes like endocytosis (the formation of vesicles from the plasma membrane). Lipid Specificity: Many BAR domains exhibit lipid specificity, meaning they preferentially bind to certain types of lipids, such as phosphoinositides (e.g., PIP2 or PIP3). These specific lipids often serve as molecular markers that direct the BAR domain to specific membrane regions, such as membrane deformation. The specificity enhances the binding affinity and helps regulate the spatial and temporal localization of the BAR domain proteins within the cell. Oligomerization: BAR domains can oligomerize, meaning they can bind together to form higher-order structures. This property is important for creating larger scaffolds that stabilize extensive curved membrane regions.

13. Functions of BAR Domain

14. Following are the function that are performed by BAR Domain : Membrane remolding Endocytosis( Clathrin -mediated endocytosis) Vesicle Trafficking & Membrane Tubulation Cellular Signaling

15. 1. Membrane remolding: Membrane Curvature Sensing : The BAR domain's curved structure allows it to bind preferentially to pre-existing curved regions of membranes. The positively charged concave surface of the BAR domain interacts with the negatively charged phospholipid head groups in the membrane, stabilizing its attachment. This interaction enables the BAR domain to sense specific membrane curvatures.

16. Membrane Curvature Induction: Upon binding to flat membrane surfaces, they can force the lipid bilayer to bend into a curved shape. This happens because the BAR domain's dimerized, banana-shaped structure imposes its curvature on the membrane, driving the formation of tubular or vesicular structures.

17. 2. Endocytosis In clathrin -mediated endocytosis, clathrin coats the budding vesicle. BAR domain proteins often work in conjunction with clathrin and other accessory proteins, helping to generate and stabilize the curvature necessary for vesicle formation.

18. 3. Vesicle Trafficking & Membrane Tubulation BAR domain proteins are heavily involved in the formation of endosomes — membrane-bound compartments that sort and transport cellular material. For instance, sorting nexins (SNXs), which contain BAR domains, help shape the tubular endosomal membranes and aid in the trafficking of proteins and lipids

19. 4. Cell Singling During this process, they also recruit proteins involved in signaling, such as dynamin , which is essential for vesicle scission. BAR domain proteins often interact with small GTPases , such as Rho and Ras family members , which are key regulators of various signaling pathways. BAR domain-containing proteins such as Endophilin and Syndapin regulate synaptic vesicle endocytosis and recycling, which are critical for neurotransmission.

20. What kind of diseases occurs due to abnormality in function? Neurological Disorders : Amphiphysin -associated stiff-person syndrome Autoimmune disorder Cancer Abnormal function of BAR domains in proteins like Endophilin and Bin1 is associated with various cancers. breast cancer melanoma. Cardiomyopathy Arfaptin 2 , have been implicated in heart diseases like dilated cardiomyopathy, affecting the heart's ability to pump blood efficiently. dilated cardiomyopathy

21. Future Directions: BAR domain function has been linked to diseases like neurodegenerative disorders, cancer, and cardiovascular diseases. Future research could explore BAR domains as potential therapeutic targets for drug development, focusing on how modulating their activity might restore normal cellular functions. BAR domains could be engineered for use in artificial systems to model membrane dynamics or in the development of nanotechnology applications, such as the creation of nano -carriers for drug delivery systems that rely on vesicle formation and trafficking .