Internal motions prime cIAP1 for rapid activation
Aaron H Phillips1, Allyn J Schoeffler1, Tsutomu Matsui2
1Department of Early Discovery Biochemistry, Genentech, South San Francisco, California, USA.
Nature Structural & Molecular Biology
|November 11, 2014
Summary
Cellular inhibitor of apoptosis 1 (cIAP1) dynamics reveal its activation mechanism. Micro- and millisecond motions enable rapid, peptide-induced opening and dimerization, challenging the static binary switch model.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Cellular inhibitor of apoptosis 1 (cIAP1) is a ubiquitin ligase crucial for regulating programmed cell death and NF-κB signaling.
- cIAP1 is typically an autoinhibited monomer that dimerizes, activates, and degrades upon proapoptotic signals, a view based on static structures.
- The dynamic nature of cIAP1 activation has remained largely unexplored due to limitations of static structural studies.
Purpose of the Study:
- To investigate the dynamic motions within human cIAP1 at micro- and millisecond timescales.
- To observe the global conformational changes associated with cIAP1 activation.
- To elucidate the mechanism by which cIAP1 transitions from an autoinhibited state to an active dimer.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy to probe micro- and millisecond motions at specific domain interfaces.
- Time-resolved Small-Angle X-ray Scattering (TR-SAXS) to capture global conformational changes during activation.
Main Results:
- Motions within the interfaces of the closed cIAP1 monomer are insufficient for direct activation but facilitate interactions with partners.
- These dynamics enable rapid, peptide-induced opening and subsequent dimerization of cIAP1.
- A significant, spring-loaded structural transition accompanies the activation process.
Conclusions:
- cIAP1 activation is a dynamic process involving internal domain motions that prime the protein for interaction and conformational change.
- The study proposes a revised model of cIAP1 activation, emphasizing its dynamic nature over a simple binary switch.
- Understanding cIAP1 dynamics offers new insights into its roles in cell death and signaling pathways.
More Related Videos
09:52Measuring and Manipulating Functionally Specific Neural Pathways in the Human Motor System with Transcranial Magnetic Stimulation
Published on: February 23, 2020
10.0K
09:55All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System
Published on: December 20, 2021
3.5K
Related Concept Videos
01:15Activation of Integrins
5.8K
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...
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...
5.8K
01:22Activation and Inactivation of G Proteins
12.8K
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
12.8K
01:11IP3/DAG Signaling Pathway
16.2K
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
16.2K
01:17Intracellular Signaling Affects Focal Adhesions
3.9K
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...
3.9K
01:15Muscle Contraction
101.6K
101.6K
01:10Muscle Contraction
9.5K
In skeletal muscles, acetylcholine is released by nerve terminals at the motor endplate—the point of synaptic communication between motor neurons and muscle fibers. The binding of acetylcholine to its receptors on the sarcolemma allows entry of sodium ions into the cell and triggers an action potential in the muscle cell. Thus, electrical signals from the brain are transmitted to the muscle. Subsequently, the enzyme acetylcholinesterase breaks down acetylcholine to prevent excessive...
9.5K