Isoaspartate-dependent molecular switches for integrin-ligand recognition
1Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy. corti.angelo@hsr.it
Journal of Cell Science
|February 2, 2011
Summary
Isoaspartyl residue formation in extracellular matrix proteins can enhance integrin recognition. This post-translational modification at specific sites may mimic known binding motifs, impacting cell adhesion and drug interactions.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- Integrins are crucial cell-adhesion receptors mediating interactions with the extracellular matrix (ECM) and other cells.
- Integrin-ligand recognition is key to cellular processes but can be modulated by protein modifications.
- Isoaspartyl residue (isoAsp) formation is a spontaneous post-translational modification affecting protein structure and function.
Purpose of the Study:
- To review recent studies on isoAsp formation in integrin ligands.
- To discuss the regulatory role of isoAsp formation in integrin-ligand recognition.
- To explore the biological and pharmacological implications of isoAsp formation at specific amino acid motifs.
Main Methods:
- Review of existing experimental evidence and scientific literature.
- Analysis of the structural and functional consequences of isoAsp formation.
- Discussion of the mimicry between isoAsp-containing sequences and known integrin-binding motifs.
Main Results:
- Isoaspartyl residue formation at Asn-Gly-Arg (NGR) sites can create an isoAsp-Gly-Arg (isoDGR) sequence.
- The isoDGR sequence can act as a gain-of-function modification, mimicking the Arg-Gly-Asp (RGD) integrin-binding motif.
- This transition occurs in vitro in natural proteins and drugs, promoting integrin recognition and cell adhesion.
Conclusions:
- IsoAsp formation represents a novel regulatory mechanism for integrin-ligand interactions.
- The NGR-to-isoDGR transition has significant implications for understanding ECM protein function and drug design.
- Further investigation is warranted into the effects of isoAsp formation at various sites (NGR, DGR, RGD) on integrin recognition and biological outcomes.
Related Concept Videos
01:15Activation of Integrins
Integrins bind ligands and transmit information from outside the cell to inside or vice-versa through an "outside-in signaling" or "inside-out signaling."
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding events provide an effective stimulus.
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding events provide an effective stimulus.
01:17Intracellular Signaling Affects Focal Adhesions
Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...
Some...
00:49Ligand Binding and Linkage
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...
00:49Ligand Binding and Linkage
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...
01:10Integrins
Animal and protozoan cells do not have cell walls to help maintain shape and provide structural stability. Instead, these eukaryotic cells secrete a sticky mass of carbohydrates and proteins into the spaces between adjacent cells. This network of proteins and molecules is called an extracellular matrix or ECM.
Some ECM proteins assemble into a basement membrane to which the remaining components adhere. Proteoglycans typically form the bulk of the ECM while fibrous proteins, like collagen,...
Some ECM proteins assemble into a basement membrane to which the remaining components adhere. Proteoglycans typically form the bulk of the ECM while fibrous proteins, like collagen,...
01:30Assembly of Signaling Complexes
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...