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Calcium dependent interactions of calponin homology domains (CHD)

Calcium dependent interactions of calponin homology domains (CHD)

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An essay for the 2011 Undergraduate Awards (Lecturer Nomination) Competition by Therese Mallon. It is nominated by Lecturer David Timson of Queen's University Belfast in the category of Life Sciences
An essay for the 2011 Undergraduate Awards (Lecturer Nomination) Competition by Therese Mallon. It is nominated by Lecturer David Timson of Queen's University Belfast in the category of Life Sciences

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Published by: Undergraduate Awards on Sep 01, 2012
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Calcium dependent interactions of calponin homologydomains (CHD)
 There has been continuous debate about the details of calponinhomology domain interactions and their dependency on calcium. Calponinhomology domains were identified in a variety of proteins from actin cross-linking to signalling. The reliance on calcium and calcium-calmodulin forthese interactions is discussed and was found to be necessary withinvarious proteins. The FLNa actin-binding domain only dissociated from F-actin when bound to Ca
-Calmodulin and was found to be necessarywithin the calponin homology domain in Vav1 allowing for functionalcoordination of Vav1 and CaM in calcium signalling. However othercalponin homology domains did not demonstrate reliance on Ca
-Calmodulin for their interactions. The SMTNL1 protein showed extremelyweak or no binding of Ca
-CaM indicating that the calponin homologydomain is not dependent on Ca
-CaM. Within proteins includingmicrotubules, it has not yet been established whether the interactions aredependent on Ca
-CaM, indicating that there is room for furtherdevelopment and research.
1. Introduction
 The calponin homology domain (CHD) is one of about a dozenprotein domains which are shared by both signaling and cytoskeletonproteins.
 They are termed CHD due to their homology to the N-terminaldomain in calponins, actin binding proteins that regulate smooth musclecontraction.
 They have been identified in a variety of proteins and areproposed to function either as actin binding motifs or serve as regulatoryfunction. The CHD is defined by a number of almost invariant coreresidues. These core residues are likely to be the major factors involved instabilizing the three-dimensional structure.
 These residues have beenconserved throughout species indicating an evolutionary conserved1
structure. Although the various CHD share relatively little amino acidsequence identity, a number of strictly conserved hydrophobic residuesgive rise to an almost unchanging hydrophobic core. Despite a commonoverall fold, different CHDs serve to interface with a wide variety of proteins involved in cytoskeleton dynamics and signal transduction.
CHDare classified into several families. The main calponin homology domainsare type-1 CHD, type-2 CHD and type-3 CHD. Caplonin homology domaintype-1 and type 2 are normally arranged in tandem and are found in manyactin-binding proteins. The type-2 CH domain can also exist as an isolatedCH-domain, and is found in a few proteins, including smoothelins.
 Type-3CHD is found in several proteins including IQGAP and calponin and is asingle CH domain.Within this review the structure of CHDs and its interactions withcalcium will be discussed. These interactions with calcium and calmodulinare essential for cellular communication. Calcium acts as a ubiquitousintracellular messenger responsible for controlling numerous cellularresponses. A momentary rise in intracellular calcium concentrationinduces a conformational change in calmodulin, allowing it to bind tospecific domains on target proteins, predominately amphiphilic
 The physiological effects of calponin homology domains with F-actin,Vav1, a guanine nucleotide exchange factor, smoothelin-like proteins andmicrotubules will also be introduced. The aim is to conclude whether theinteractions with the domains and proteins are dependent on calcium forcytoskeleton dynamics and signal transduction.
2. Structure of Calponin Homology Domains
 The architecture of the CHD is dominated by four
-helices. These
-helices are comprised of 11-18 residues and are connected by long loops. There are also three short and less regular helices, which are minorsecondary structural elements. The structure can be described in terms of three layers, the core being composed of two parallel
-helices which are2
sandwiched by two helices one being the N-terminal helix (A) and theother tilted with respect to the core helices direction by approximately20
A very conserved region of the molecule is helix C that builds thehydrophobic core of the protein. This segment belongs to a sequenceprofile that has been used for detection of CHDs in proteins.
Anextensive aromatic stacking seems an important feature for thestabilisation of the core:
-spectrin CHD containing 13 aromatic residues.
Helix A is located on the surface of the protein, helping to bury helix Cand interacting tightly with helix G. The interface involves several van derWaal’s interactions between residues that are well conserved within the C-terminal CHDs of 
-actinin but less conserved in the N-terminal CHDs or inthe singular CHD of signalling proteins, implying that local rearrangementsof the helix packing can be seen between the sub-classes of the family.
 There is additional stabilisation by a salt bridge between charged residueson the N and C-terminal helices.
Figure 1
[6, 7, 8]
A ribbon diagram of calponin homology domain from human
-spectrin. Helices A-G are labelled. A, C, F and G are the main four helices; B and Eminor secondary structural elements.
3. CH1 and CH2 arranged in tandem

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