Gene name - scab
Synonyms - alphaPS3
Cytological map position -
Function - cell surface adhesion protein
Symbol - scb
Genetic map position - 2-73
Classification - alpha integrin
Cellular location - surface transmembrane
scab was initially described in a study of mutations that affect the pattern of the larval cuticle (Nusslein-Volhard, 1984). The defect in dorsal closure that describes the effects of scab mutation is similar to that seen in myospheroid mutant embryos. Myospheroid (also known as beta PS) is the dimerization partner of two previously characterized alpha integrins: alphaPS1 (Multiple edematous wings) and alphaPS2 (Inflated). Dorsal closure defect is not seen in null mutations of these two alpha integrins, indicating that some other alpha integrin must team up with betaPS during dorsal closure.
In a search for the presumed missing integrin, attention was focussed on a 90kDa band associated with immunoprecipitates of Myospheroid, resulting from the application of an anti-betaPS antiserum. This 90 kDa protein forms a non-covalent, divalent cation-dependent complex with Myospheroid. The 90 kDa protein binds well to both lentil lectin and Concanavilin A beads, suggesting that it is a glycoprotein. The protein was purified by immunoprecipitation, lecitin binding, elution and SDS gel electrophoresis and subjected to tryptic digestion; the resulting peptides were then sequenced. Degenerate primers based on the amino acid sequences were used to identify the cDNA coding for the 90 kDa protein. The sequence revealed an alpha integrin subunit that has been designated alphaPS3 (Stark, 1997). Thus, the cloning of scab, revealing as it does the gene coding for the missing integrin, completes a picture of integrin activity with the discovery of a third alpha integrin partnering Myospheroid (Stark, 1997).
Additional defects in scab embryos correspond to sites of Scab expression. The defect in tracheal development in scb embryos, and the corresponding defects in embryos lacking both maternal and zygotic Myospheroid indicate that Scab, in conjunction with Myospheroid, plays a role during the migration and fusion of tissue in tracheal development. Scab expression is also seen in the salivary glands, beginning as they invaginate from the surface of the embryo and continuing as they form a tubular structure surrounding a central lumen. After dorsal closure, expression is clearly present in some cells of the dorsal vessel. Pericardial cells lie at the edge of the epidermis during dorsal closure and later contribute to the formation of the dorsal vessel. Defects are observed in the localization of the pericardial cells in scb mutant embryos, and a similar, although more severe defect has now been identified in embryos lacking both maternal and zygotic Myospheroid. The defect in mys embryos is strikingly similar to that reported for embryos missing the laminin A chain (Yarnitzky, 1995). This supports the hypothesis that alphaPS3 and betaPS both play a role in the movement and migration of the pericardial cells during dorsal vessel formation and suggests that laminin may be a ligand during this process (Stark, 1997).
Volado is a new memory mutant of Drosophila. The locus encodes two isoforms of a new alpha-integrin, a molecule that dynamically mediates cell adhesion and signal transduction. Volado, now termed Scab, is expressed preferentially in mushroom body cells, which are neurons known to mediate olfactory learning in insects. The Vol antigen is found concentrated in the mushroom body parikarya and calyces, peduncles and alpha, beta and gamma lobes. The calyces, peduncles and lobes contain the mushroom body dedrites, axons and axon terminal, respectively. Volado proteins are concentrated in the mushroom body neuropil, the brain area that contains mushroom body processes in synaptic contact with other neurons. The distribution of the two Vol isoforms are globally coexpressed. Enriched expression is also observed in the ellipsoid body, a region of the central complex, thought to be involved in the coordination of motor behaviors. Volado mutants display impaired olfactory memories within 3 min of training, indicating that the integrin is required for short-term memory processes. Conditional expression of a Volado transgene during adulthood rescues the memory impairment. This rescue of memory is reversible, fading over time along with expression of the transgene. Thus the Volado integrin is essential for the physiological processes underlying memory. A model is proposed in which integrins act as dynamic regulators of synapse structure or are involved in the signaling events underlying short-term memory formation. It is envisioned that release of a modulatory neurotransmitter on a mushroom body neuron might mobilize the intracellular events altering the binding of integrins displayed at another synapse made by that cell. For example, protein kinase C and Ras activation are both known to activate integrin binding. Activation of either could produce a rapid (within minutes) alteration in the structure and efficacy of that synapse. The modulation of integrin affinity for ligands might also underlie the construction or pruning of existing synapses, or the activation of silent synapses during learning or memory encoding (Grotewiel, 1998).
A splice variant of Scab contains an alternative 5' end replacing the first 63 amino acids.
The Scab protein has a 24 amino acid N-terminal signal sequence followed by a large (1033 amino acid) extracellular domain, a single transmembrane domain (23 amino acid) and a short (35 amino acid) cytoplasmic tail. The extracellular domain contains seven repeats common to all alpha integrin subunits. The alternate 5' splice has a 25 amino acid signal sequence followed by 38 amino acids and terminates in the first repeat. The last three repeats each contained a consensus divalent cation-binding motif Dx(D/N)x(D/N)GxxD for alpha integrins. A degenerate site is seen at position 262, between alpha repeats 3 and 4, the Gxx having been deleted. This site occurs exactly at the N terminus of the 90 kDa protein purified from Schneider L2 cells. A protein lacking the predicted structures from the first 261 amino acids would be unlikely to function as a normal integrin since a number of the conserved repeats would be eliminated. This may have been an artifact of the protein purification process, or may reflect some unusual protein variant. The 20 amino acids starting at position 195 match a motif found in a series of zinc- or cobalt-dependent enzymes. The histidine in this motif has been hypothesized to function in metal ion binding. Although functional evidence for this motif is not available, it may indicate novel divalent cation-dependence for alphaPS3. Immunoprecipitation and sucrose density gradients show that this integrin belongs to the group of alpha integrins that are cleaved external to the transmembrane domain into a light and heavy chain. The greatest homology to the consensus cleavage site (K/R)R(E/D)hydrophobic is the RRDL at position 928. A consensus cleavage site is seen in this position in alignments with human integrins alpha6, alpha7, alpha3, Scab and C. elegans F54G8.3 and nearby in human aIIb integrin. This site occurs between the conserved cysteines implicated in the disulfide bonding of the heavy and light chains, and is subsequent to the last of the tryptic sequences obtained from the putative heavy chain in Schneider L2 cells, all of which fall between amino acids 262 and 848. These lines of evidence are consistent with cleavage occurring at this site in Scab. 14 cysteine residues are present; 12 are in conserved locations, two are in novel sites and two residues, which are usually found, are absent. Nine potential N-linked glycosylation sites (NxT/S) are found in the extracellular domain. The highly conserved KxGFF(K/N)R is found just inside the putative transmembrane domain. The remainder of the cytoplasmic domain contains no striking similarity to any known protein. The sequence of Scab has no close vertebrate homolog (Stark, 1997).
date revised: 5 February 98
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