My Seminar on Saturday

7/27/2019 My Seminar on Saturday

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Seminar By : V.SIDDHARTHA REDDY

Topic : INTEGRINS

Date : Feb-26-2011

Venue : Aurora P.G College

WELCOME


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WHAT WE ARE GOING TO LEARN

What Are INTEGRINS ? How They Look Like(Structural Features)?

How They Get Activated?

Their number and classification?

Are they really useful/useless?


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WHAT ARE INTEGRINS ?

super family of cell adhesion receptors that bind

to extracellular matrix ligands , cell-surface

ligands ,and soluble ligands

Found In : Mammals

Chicken

Zebra fish

Lower Eukaryotes

*Inside out / out side in signaling


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How They Look Like(Structural Features)?


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90 kDa to 160 kDa.

N-terminal -extracellular side/C-terminal-

inside & sub-units are non homologous.

Sequence identity among subunits- 30% /

subunits-45%.(gene duplication evolution) Humans: their genes located on various

chromosomes.

Studies on Integrin genes-derived fromcommon ancestral gene by geneduplication.


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Motomu Shimaoka et al Annu. Rev. Biophys. Biomol. Struct.2002. 31:485-516.

I-Domain,(interaction/insertion)

I-like domain

*Serves as RGD domain binding

sites*RGD binding motif(asp-gly-asp).


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Drosophila:

5+1-5integrins

C.elegans:

2+1-2integrins

Humans:

18 +8 -24integrins

4/5: families

Their number andclassification?


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TEGRIN LIGAND DISTRIBUTION51 Fibronectin Ubiquitous61 Laminin Ubiquitous71 Laminin Muscle

L2 (LFA-1) Ig superfamily White blood cellsICAM-1

23 Fibrinogen Plaelets64 Laminin Epithelial

hemidesmosomes

1 subunits Partner with at least 12 subunits2 subunits WBC. Cell-cell adhesion. Ig superfa

tegrin Binding Specificities


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Cell Junction Function

1. Tight (Occluding)

JunctionsSeals neighboring cells together in

an epithelial sheet to prevent

leakage of molecules between

them2. Anchoring Junctions

Adherens Junction Joins an actin bundle in one cell

to an actin bundle in a neighboring

cell

Desmosome Spot weld that anchors the

intermediate filaments in one cell

to those in a neighboring cellHemidesmosome Anchors intermediate filaments in acell

to the basal lamina or underlying

extracellular matrix

3. Communicating

Junctions

Gap Junction Cell-cell junction which allows thepassage of small water-soluble ions

and molecules & electrical signals

Chemical Synapse Facilitates a type of

neurotransmission

Focal Adhesion Attaches actin filaments in a cell to

extracellular matrix


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Focal Contacts Integrins perform their

work by focal contacts.

Link extracellular matrixto actin filaments

Allows cells to hang on tosurroundings

Bind to actin indirectly viaanchor proteins

Actin Vinculin

amellapodia Focal Contacts Movie3-GFP

CB 155: 1319, 2001.


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How They Get Activated?

mustbeactivatedinorderto

bindtotheECM

Talin


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Rap-mediated integrin activation.

Contd..next slide


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Rap canactivate(straightening)/inactivate(clustering) towards the

stimuli(agonistic/antagonistic). Rap=Ras

Total Integrin Affinty: no.of active vsinactive forms.

Contnd..


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Are they really useful/useless?

(Yep!! they are not useless like us, they performvarious functions.)

Cell mobility/wound healing.

cell signaling(growth anddevelopment).

Leukocyte migration to the site ofinflammation.


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How can integrins affect cell motility?

The integrins can only bind to their binding partners when there is a minimumnumber of integrins present at specific places known as focal contacts.

The affinity of integrins for their ligands is not very strong. Therefore, to formeffective cell-to-cell or cell-to-extracellular matrix contacts, several integrinsmust be localized at the focal contact.

Accordingly, when the integrins are diffusely distributed over the cell surface, nostrong adhesion will be present. The low affinity of integrins for their ligands isnecessary to prevent irreversible binding of cells, which would result in a lack of

motility. By making and breaking focal contacts, a cell can actually move throughits environment.


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leukocyte migration

Up-regulation of adhesion molecules on endothelial cells isinduced by an array of inflammatory mediators such as

TNF, IL-1, histamine and others produced by tissue residentinflammatory cells.

Selectins Integrins


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Integrins in epidermal cellsduring wound healing

Integrins enable epithelial cells to migrate during wound closure.

In normal epidermis, integrins alpha-2 beta-1 and alpha-3 beta-1 areinvolved in cell-to-cell contacts. This means that they causeepidermal cells to stick to each other.

During wound healing, migrating epithelial cells express new type ofintegrin,such as integrin alpha-5beta 1.

This integrin is not present in normal unwounded epidermis. Theappearance of integrin alpha-5 beta-1 starts shortly after woundingand it lasts only for a short duration.


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(64)

Normal:2131

(for cell-

cellcontact)

51For

migration


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After a while, migrating epidermal cells start dividingand proliferating in order to make epidermal cellsheets and cover the wound area. This process is

called re-epithelialization. At the same time, the epidermal cells start

producing some of the components of basementmembrane in order to stabilize the structure of

newly-formed epidermis. The fusion of movingepidermal sheets is associated with the production ofa new integrin, called alpha-v beta-6.

integrin alpha-v beta-6 is involved in reconstructionof the new basement membrane.


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After reepithelialisation:

Late production ofv6(when cellmigration stopped)from epithelialcells

v6 activates transforming growthfactor(TGF)-involved in*healing*sends signal to epidermalcells to stop dividing when their no.is

sufficient(*scar formation regulation )


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Extracellular Signalling

signaling molecules are released by signaling cells

the signal is called the ligand

the ligand binds to its specific receptor on a targetcell

this ligand-receptor interaction induces aconformational or shape-change in the receptor

produces a specific response - called the cellularresponse

can include a vast array of compounds

e.g. small amino acid derivatives, small peptides, proteins


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Cell-to-cell communication by extracellularsignaling usually involves six steps

(1) synthesis of the signaling molecule by the signaling cell

(2) release of the signaling molecule by the signaling cell

(3) transport of the signal to the target cell

(4) detection of the signal by a specific receptor protein receptor-ligand specificity

(5) a change in cellular metabolism, function, or development =

cellular response triggered by the receptor-ligand complex specific to the ligand-receptor

complex

(6) removal of the signal, which usually terminates the cellular

response degredation of ligand


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My Seminar on Saturday

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