The Structural Dynamics, Complexity of Interactions, and Functions in Cancer of Multi-SAM Containing Proteins

Abstract

SAM domains are crucial mediators of diverse interactions, including those important for tumorigenesis or metastasis of cancers, and thus SAM domains can be attractive targets for developing cancer therapies. This review aims to explore the literature, especially on the recent findings of the structural dynamics, regulation, and functions of SAM domains in proteins containing more than one SAM (multi-SAM containing proteins, MSCPs). The topics here include how intrinsic disorder of some SAMs and an additional SAM domain in MSCPs increase the complexity of their interactions and oligomerization arrangements. Many similarities exist among these MSCPs, including their effects on cancer cell adhesion, migration, and metastasis. In addition, they are all involved in some types of receptor-mediated signaling and neurology-related functions or diseases, although the specific receptors and functions vary. This review also provides a simple outline of methods for studying protein domains, which may help non-structural biologists to reach out and build new collaborations to study their favorite protein domains/regions. Overall, this review aims to provide representative examples of various scenarios that may provide clues to better understand the roles of SAM domains and MSCPs in cancer in general.

Keywords: CASKIN; Eph receptors; LAR-RPTP; Liprin; SASH1; cancer; disordered SAM domains; metastasis; tumor suppression.

Figure 1

Domain architecture of MSCP proteins and families. Proteins are aligned by final SAM domain. Sizes are relative and not to scale. Representative protein members are shown here for each family. Stars indicate SAM domains with experimentally shown disordered states.

Figure 2

Binding of the disordered SAM domain in tandem with a well-folded SAM domain leads to a heightened level of complexity in the system. Schematic representation illustrating the potential impact of having two SAM domains in tandem. In isolation, the disordered SAM domain (domain A: depicted in red) exhibits higher conformational flexibility. However, upon interacting with a folded SAM domain (domain B: illustrated in blue), a dimer is formed, accompanied by folding of the disordered domain. This event may result in the formation of higher-order polymeric structures crucial for the functioning of the system.

Figure 3

Diversity in multimerizations of the MSCPs’ SAMs. (A) The ANKS1B tandem SAM1/2 domain (PDB: 2KIV) forms an intramolecular head-to-tail monomer. SAM2 is disordered when not bound to SAM1, which may serve to regulate the nuclear localization sequence (yellow) in helix 5 of SAM2. (B) Liprin-α and Liprin-β each has three tandem SAM domains that intramolecularly trimerize (PDB: 3TAD). SAM3 of Liprin-β can dimerize with SAM1 of Liprin-α, creating a Liprin heterodimer and a linear SAM hexamer in a head-to-tail fashion. (C) CASKIN1 tandem SAM1/2 (PDB: 3SEN) forms intramolecular head-to-tail interactions that then extend to other CASKIN2 tandem SAM1/2 domains to form a helical oligomer of monomers. (D) The tandem SAM1/2 domain of CASKIN2 (PDB: 5L1M) forms intermolecular interactions to form a dimer that may expand to an oligomer of dimers. This “domain-swapped dimer” can lead to a branched oligomer in contrast to CASKIN1′s spiral oligomer. (E) The SARM1 tandem SAM1/2 (PDB: 6QWV) form intramolecular head-to-tail interactions that then utilize lateral interactions to form a stacked closed octameric ring.

Figure 4

Schematic for approaching the study of MSCP SAM domains. The numbers at the end indicate the subsections.

Figure 5

The Alpha-Fold predicted structure of SASH1′s C-terminal (1082–1247). This includes the SAM2 domain (1177–1241; red) and a novel SAM-like helical bundle (1092–1170; cyan).