SerpinB5, also known as maspin, is considered a tumor suppressor serpin that does not present itself as a protein inhibitor like others of its own family, the serine protease inhibitor superfamily (serpins). Maspin was first identified in 1994 on mammary tissue and breast cancer cell lines (1), but it is also known to be expressed on a wide range of cell types and tissues, mainly in epithelial cells, i. e. in prostate, lung, skin, and corneal stromal cells (2). It differs from ordinary serpins once it does not undergo the stressed (S) to relaxed (R) conformation which is a striking feature of other proteins in serpin’s superfamily. Instead, its G-helix has quite a flexibility, capable of changing the conformation of the protein itself.

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Maspin and its superfamily

Serpins

Serpins usually inhibit other proteins like serine proteases, caspases and papain-like cysteine proteases, however, some of them do not accomplish an inhibitory role (3). As an example, some of them function as hormone transporters, molecular chaperones or even as tumor suppressors (3). Serpins structure usually contain three ß-sheets (A, B and C) and eight to nine 𝛂-helices (hA-hI) on their structure, and the most important region to interact with their targets is the reactive center loop (RCL) (An overview of the serpin superfamily). Inhibitory serpins are considered “suicide molecules” because they can only be used once (Huntington, J., Read, R. & Carrell, R. Structure of a serpin–protease complex shows inhibition by deformation . Nature 407, 923–926 (2000). https://doi.org/10.1038/35038119). The RCL is usually positioned out of the body of the serpins. When inhibiting proteases, serpins get their RCL cleaved out of the main structure, causing the amino-terminal portion of the RCL to form an additional fourth strand called s4A, once it is inserted into the center of ß-sheet A. This cleavage and modification on the structure of serpin is called the ‘stressed (S) to relaxed (R) transition’, in which the protein is in its biologically active state and transitions to a more thermal stable and latent state, respectively (An overview of the serpin superfamily).

Maspin

Maspin is a 42 kDa protein (Zou Z, Anisowicz A, Hendrix MJ, et al. Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells. Science 1994; 263: 526–9.) and is inserted in clade B of the serpin superfamily, composed of papain-like enzymes and inhibitory serpins that target cytotoxic apoptotic proteases which are working incorrectly (3). Differently from other serpins, Maspin does not undergo the S to R transition (An overview of the serpin superfamily). Instead, its G-helix is capable of undergoing a significant conformational change, that means this region of the molecule has some flexibility that allows movement. However, it is important to mention that studies have demonstrated, by superposing all of the maspin chains, a conformational heterogeneity at and around the G-helix (The High Resolution Crystal Structure of the Human Tumor Suppressor Maspin Reveals a Novel Conformational Switch in the G-helix). Also maspin is not limited to a certain cell compartment, once it is found on nucleus, cytoplasm, membrane, and as a secreted protein, according to the cell type and tissue (1)(2). Currently, it is known that the subcellular location of maspin is important for its tumor suppressor activity, and not only its protein levels inside the cell. In the past, there was a controversy about it, once maspin was upregulated in some tumors, while downregulated in others (Nuclear localization of maspin is essential for its inhibition of tumor growth and metastasis). Then, its translocation to the nucleus was observed and maspin’s nuclear localization was related to its tumor suppressor function, (Nuclear localization of maspin is essential for its inhibition of tumor growth and metastasis). However, contrary to what is expected, it has never been found a nuclear localization sequence (NLS), nuclear export sequence (NES), neither a secretory leader sequence (SLS) on maspin structure (Bodenstine TM, Seftor REB, Khalkhali-Ellis Z, Seftor EA, Pemberton PA, et al. (2012) Maspin: molecular mechanisms and therapeutic implications. Cancer and Metastasis Reviews 31: 529–551.). The tumor suppressor function of maspin is probably related to its activities, which are mainly inhibition of cell growth, invasion, tumoral migration, apoptosis stimuli, gene transcription regulation, angiogenesis inhibition (4) and prevention of oxidative damage of the proteome (5). Besides all of these functions, maspin also has an important role in the organization of the epiblast during early embryonic development (The High Resolution Crystal Structure of the Human Tumor Suppressor Maspin Reveals a Novel Conformational Switch in the G-helix). However, maspin lacks studies on non-tumoral cell lines, and its role on a normal condition might be different from its activity inside a tumoral lineages.

Function

Disease

Relevance

Structural highlights

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