Spectrin repeats. Protein Motifs Session FRCPath Preparation Course 10/12/09. FEBS Letters Volume 513, Issue 1, 20 February 2002. Spectrin repeats (SR). Large modular repeat elements found in protein members of the spectrin superfamily.
Protein Motifs Session
FRCPath Preparation Course
Spectrin repeats (SR)
Large modular repeat elements found in protein members of the spectrin superfamily
Consist of 3 helices (A, B, C) that are separated by two loop regions (AB, BC) and arranged in a left handed triple helical bundle.
Approx. 100 amino acids in each repeat
Low sequence identity between repeats but all share similar 3D structure
Common key conserved residues involved in the hydrophobic and electrostatic interactions that stabilise the bundle
- invariant Tryptophan residue at position 17 of Helix A
- highly conserved charged residues in all helices
- a nearly invariant Tryptophan in the middle of Helix C
- a Leucine residue at carboxyl end of Helix C
There is a sequence of a few residues linking each repeat to the next
Thought to have originated through duplication events of the exons coding the original progenitor SR
Variation between repeats is suggestive of specialised functions.
SR are also found in unrelated proteins involved in signalling pathways
Examples include kalirin, MCF2 (dbl-protooncogene), PLEKHG4 (puratrophin-1)
Structural role in assembly of complex proteins involved in cytoskeletal and signal transduction complexes
- maintenance and modelling of cytoskeleton and organelles
- organisation of networks of multiprotein interactions
Mechanical properties – Elastic, flexible, dynamic
- important in cytoskeletal proteins that are exposed to great mechanical stress
Binding sites for interaction with other proteins
Cytoskeletal protein found in many cell types. Present in both vertebrates and invertebrates.
Links plasma membrane to the actin cytoskeleton
7 genes in humans:
- subunit : SPTA1 (erythrocyte isoform), SPTAN1
- subunit : SPTB (erythrocyte isoform), SPTBN1, SPTBN2, SPTBN4, SPTBN5
Composed of two antiparallel dimers of - and - subunits (tetramer formation)
- and - subunits assembled in dimers in a head to tail mode
Dimers arranged in a tetramer in a head to head manner
Red blood cell - spectrin based cytoskeleton
Triangulated 2D meshwork composed of spectrin tetramers that are crosslinked by actin in association with accessory proteins.
Spectrin in disease (1)http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A1861
Hereditary Spherocytosis (HS): Spherical-shaped RBC (spherocytes) on the peripheral blood smear.
Anaemia, jaundice, and splenomegaly, with variable severity. Common complications include cholelithiasis, hemolytic episodes, and aplastic crises. Recessive
Hereditary Elliptocytosis (HE):Oval-shaped RBC
Variable degree of haemolytic anaemia. Dominant
Hereditaty pyropoikilocytosis (HPP): microspehrocytosis, poikilocytosis and thermal sensitivity of RBC. Severe presentation in infancy progression to elliptocytosis in later life. Recessive
Spectrin in disease (2)http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A1861
Molecular Therapyhttp://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A1861 (2006) 13, 241–249
Dystrophin provides a structural and signalling link between the extracellular matrix and the intracellular actin cytoskeleton
In DMD/BMD, partial deletions and duplications cluster in two recombination hot spots, one proximal at the 5' end of the gene exons 2-20 (30%), and one more distal exons 45-53 (70%)
- DMD: 60% deletions, 5% duplication, remaining point mutations
- BMD: 80% deletion, 10% duplications, remaining point mutations
DMD: Mutations that lead to lack of dystrophin expression
BMD: Mutations that lead to abnormal quantity or quality
Nesprins in diseasehttp://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A1861
Speicher and Ursitti 1994. Conformation of a mammoth protein. Current Biology Vol 4 No 2 p:154.
Djinovic-Carugo et al 2002. The spectrin repeat: a structural platform for cytoskeletal protein assemblies. FEBS Letters Volume 513, Issue 1, 20 February 2002
Young and Kothary 2005. Spectrin repeat proteins in the nucleus. BioEssays 27: 144-152
Stabach et al 2009. The structure of ankyrin-binding site of -spectrin reveals how tandem spectrin repeats generate unique ligand-binding properties. Blood Vol 113, No 22 p:5377
Pascual Castrenasa and Saraste 1997. Evolution of the spectrin repeat. BioEssays 19: 811-817
De Matteis and Morrow 1998. The role of ankyrin and spectrin in membrane transport and domain formation. Current Opinion in Cell biology 10: 542
Ahn and Kunkel 1993. The structural and functional diversity of dystrophin. Nature Genetics Vol 3 p:283