r r r Cell Signalling Biology Michael J. Berridge Module 4 Sensors and Effectors 4 1
Module 4 Sensors and Effectors
Synopsis
Signalling pathways regulate cellular processes by acting through sensors to stimulate the downstream effectors that are responsible for controlling different cellular processes. In some cases, these effectors might be relatively simple, consisting of a single downstream effector system, whereas there are more complicated effectors made up of multiple components such as those driving processes such as membrane and protein trafficking, endocytosis, exocytosis, phagocytosis, motor proteins, gene transcription, gene silencing and actin remodelling.
Sensors Calmodulin (CaM) + Intracellular sensors detect the signals coming from the Calmodulin (CaM) is one of the major Ca2 sensors different signalling pathways (Module 2: Figure cell sig- in cells. It contains four helix–loop–helix folding motifs + nalling pathways) and use the information to stimulate the containing EF-hand Ca2 -binding sites (Module 4: Fig- effectors that bring about different cellular processes. ure EF-hand motif). These sites are arranged into two There are many different sensors: lobes (the N- and C-terminal lobes) at either end of the + molecule separated by a flexible linker (Module 4: Fig- • The Ca2 signalling system employs a range of different + ure CaM structure). Each lobe has two EF-hands with Ca2 sensors: sites I and II in the N-terminal domain and III and IV Calmodulin (CaM) in the C-terminal domain. The latter two sites have a Troponin C (TnC) 2 + 2 + Ca affinity that is 10-fold higher than for sites I and Neuronal Ca sensor (NCS) proteins + II. When Ca2 binds to these lobes, the molecule under- Ca2 + -binding proteins (CaBPs) goes a pronounced conformational change that exposes Calcium and integrin binding protein 1 (CIB1) a hydrophobic pocket and increases its affinity for its S100 proteins various targets that have characteristic CaM-binding do- Annexins mains. In effect, the N- and C-terminal lobes wrap them- Synaptotagmins selves around the CaM-binding domains of their effector • The regulatory subunit of protein kinase A (PKA) binds proteins to induce the conformational changes respons- the second messenger cyclic AMP [Module 2: Figure ible for altering the activity of many different signalling protein kinase A (PKA)]. components: • In the case of protein kinase C (PKC), which responds 2 + to both diacylglycerol (DAG) and Ca ,theenzymeis • Opening of intermediate-conductance (IK) and small- both the sensor and the effector (Module 2: Figure PKC conductance (SK) K + channels (Module 3: Figure structure and activation). IK/SK channel opening) • The sensors for cyclic GMP are located on its two • CaV1.2 L-type channel (Module 3: Figure CaV1.2 L- main effectors: cyclic GMP-dependent protein kinase type channel). (cGK) and the cyclic nucleotide-gated channel (CNGC) • Ca2 + /calmodulin-dependent protein kinases (CaMKs) (Module 3: Figure cyclic nucleotide-gated channels). • Myosin light chain kinase (MLCK) • The many sensors, which function in protein-lipid inter- • Phosphorylase kinase actions, have lipid-binding domains capable of sensing • Activation of NO synthase (Module 2: Figure NO syn- different lipid messengers (Module 6: Figure modular thase mechanism) lipid-binding domains). • Neuromodulin • Ca2 + sensors Neurogranin + • Ras guanine nucleotide release-inducing factors For the Ca2 signalling pathway, there are a number + (RasGRFs) of Ca2 sensors, such as troponin C (TnC), calmodulin • Human vacuolar protein sorting 34 (hVps34) (CaM), annexins, S100 proteins and the synaptotagmins. Green text indicates links to content within this module; blue text indicates links to content in other modules. EF-hand 2 + Please cite as Berridge, M.J. (2012) Cell Signalling Biology; The EF-hand is one of the major Ca -binding regions + doi:10.1042/csb0001004 found on many of the Ca2 sensors. It takes its name