The structure of S100A11 fragment explains a local structural change induced by phosphorylation

Abstract

S100A11 protein is a member of the S100 family containing two EF-hand motifs. It undergoes phosphorylation on residue T10 after cell stimulation such as an increase in Ca(2+) concentration. Phosphorylated S100A11 can be recognized by its target protein, nucleolin. Although S100A11 is initially expressed in the cytoplasm, it is transported to the nucleus by the action of nucleolin. In the nucleus, S100A11 suppresses the growth of keratinocytes through p21(CIP1/WAF1) activation and induces cell differentiation. Interestingly, the N-terminal fragment of S100A11 has the same activity as the full-length protein; i.e. it is phosphorylated in vivo and binds to nucleolin. In addition, this fragment leads to the arrest of cultured keratinocyte growth. We examined the solution structure of this fragment peptide and explored its structural properties before and after phosphorylation. In a trifluoroethanol solution, the peptide adopts the alpha-helical structure just as the corresponding region of the full-length S100A11. Phosphorylation induces a disruption of the N-capping conformation of the alpha-helix, and has a tendency to perturb its surrounding structure. Therefore, the phosphorylated threonine lies in the N-terminal edge of the alpha-helix. This local structural change can reasonably explain why the phosphorylation of a residue that is initially buried in the interior of protein allows it to be recognized by the binding partner.

The importance of Ca2+/Zn2+ signaling S100 proteins and RAGE in translational medicine

“…However it might play the role of tumor suppressor in bladder and renal carcinoma (333,334). In normal cells such as human keratinocytes, it also triggers growth inhibition through its phosphorylation by protein kinase C (Table 1) (324,(335)(336)(337).…”

The importance of Ca2 Zn2 signaling S100 proteins and RAGE in translational medicine

“…However it might play the role of tumor suppressor in bladder and renal carcinoma (333,334). In normal cells such as human keratinocytes, it also triggers growth inhibition through its phosphorylation by protein kinase C (Table 1) (324,(335)(336)(337). S100A11 has also been shown to play a role in osteoarthritis (OA) via the interaction with RAGE and the activation of the p38 MAPK pathway (338).…”

Non-Cationic Proteins Are Associated with HIV Neutralizing Activity in Genital Secretions of Female Sex Workers

“…S100A11 is also a member of the S100 family, a calcium ion-binding protein expressed by epithelial cells. S100A11 has a dual functionality in keratinocyte growth regulation such that when it is found intracellularly, it suppresses growth and facilitates differentiation and cornification of keratinocytes [ 56 ], whereas when it is found extracellularly, it in fact promotes keratinocyte growth [ 57 ]. Mucin-5AC (MUC5AC) is a glycoprotein secreted on mucosal surfaces generating another physical protective barrier against microorganisms.…”