Abstract
Sterile alpha motif (SAM) domains are protein interaction modules that are involved in a diverse range of biological functions such as transcriptional and translational regulation, cellular signalling, and regulation of developmental processes. SH3 domain-containing protein expressed in lymphocytes 1 (SLy1) is involved in immune regulation and contains a SAM domain of unknown function. In this report, the structure of the SLy1 SAM domain was solved and revealed that this SAM domain forms a symmetric homodimer through a novel interface. The interface consists primarily of the two long C-terminal helices, α5 and α5′, of the domains packing against each other. The dimerization is characterized by a dissociation constant in the lower micromolar range. A SLy1 SAM domain construct with an extended N-terminus containing five additional amino acids of the SLy1 sequence further increases the stability of the homodimer, making the SLy1 SAM dimer two orders of magnitude more stable than previously studied SAM homodimers, suggesting that the SLy1 SAM dimerization is of functional significance. The SLy1 SAM homodimer contains an exposed mid-loop surface on each monomer, which may provide a scaffold for mediating interactions with other SAM domain-containing proteins via a typical mid-loop–end-helix interface.
Highlights
The multifunctional adaptor protein SLy1 (SH3 domain-containing protein expressed in lymphocytes 1), known as SASH3 (SAM and Src homology 3 (SH3) domain containing protein 3), is exclusively expressed in lymphocytes and plays different roles in various lymphocyte subsets[1,2]
SAMC differs from samples with different loading concentrations (SAMwt) by an S320C amino acid exchange, which is located outside the predicted Sterile alpha motif (SAM) domain
SAMwt exists in a monomer-dimer equilibrium with a Kd of 117 μM as determined by Analytical ultracentrifugation (AUC), which was supported by Microscale thermophoresis (MST) results
Summary
The multifunctional adaptor protein SLy1 (SH3 domain-containing protein expressed in lymphocytes 1), known as SASH3 (SAM and SH3 domain containing protein 3), is exclusively expressed in lymphocytes and plays different roles in various lymphocyte subsets[1,2]. Murine and human SLy1 show 94% sequence identity, and the amino acid sequence of the SAM domain is identical in both proteins[1] Both SH37 and SAM8,9 domains have been shown to mediate protein-protein interactions in other proteins[9,10,11]. SAM domains contain ~70 amino acids and share a common structural motif of five helices[8,9]. They are found in a multitude of proteins in organisms ranging from yeast to mammals and are involved in diverse www.nature.com/scientificreports/. Immune adapter SLP-76 (Src homology 2 domain-containing leukocyte protein of 76 kDa) self-association in response to T-cell receptor ligation is mediated by its N-terminal SAM domain[30]. We hypothesize that dimerization of SLy1 is required for its biological function and that the SAM domain plays a role in this process
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