Structures of Zn 2+ -loaded Ca 2+ -S100B

We have determined the structures of Zn²⁺-Ca²⁺-loaded human-S100B at pH 6.5, 9.0 and 10.0 (3.4.5. Table. 2). The protein crystallized in the presence of equimolar amounts of Zn²⁺ (one Zn²⁺ per subunit) and excess amounts of Ca²⁺. The structures revealed a high-occupancy sites for both Zn²⁺ and Ca²⁺. There are two Zn²⁺ ions and four Ca²⁺ ions bound per dimer. The overall fold of the human Zn²⁺-Ca²⁺-S100B is similar to that of other S100 proteins like the human Zn²⁺-Ca²⁺-S100A7 and the Cu²⁺-Ca²⁺-S100A12 structure (3.4.5.Fig. 5 C). The overall folds of the three presented structures are virtually identical. Figure 1 A (3.4.5.). The Ca²⁺ ions are bound in the two EF-hands, whereas the Zn²⁺ ions are bound at interface of the subunits (3.4.5. Fig. 2 A-C). The structure of Zn²⁺-Ca²⁺-loaded human S100B is very similar to the structures of S100B in complex with Ca²⁺ or Ca²⁺ and peptides derived from target proteins like TRTK-S100B (1MWN), NDR-S100B (1PSB) and p53^367-388 (1DT7) (Bhattacharya et al., 2003; Inman et al., 2002a; Rustandi et al., 2000a). However, there are some noticeable differences between the X-ray structures of Zn²⁺-Ca²⁺-S100B when compared to other structures of S100B. In a recent study, it was shown that binding of Zn²⁺ to Ca²⁺-loaded S100B leads to the formation of a kink in helixIV, close to their C-terminus and that the dimers rearrange to a denser packing, in the zinc loaded state (3.4.5. Fig. 1 C) (Wilder et al., 2005). The structures of human Zn²⁺-Ca²⁺-S100B presented in this study, revealed neither a kink formation nor a denser packing. Remarkably, the binding of Zn²⁺ to Ca²⁺-S100B results only in a minor rearrangement of the C-terminus, which induces an elongation of helix IV by 5 residues compared to Zn²⁺ free Ca²⁺-S100B (3.4.5.Fig. 1 A and 3). CD spectra of S100B in the Ca²⁺ loaded and Zn²⁺-Ca²⁺-loaded state were recorded and compared. In general, the CD spectra of Ca²⁺-S100B are very similar to those of Zn²⁺-Ca²⁺-S100B.

Nevertheless, upon addition of Zn²⁺ there was a minor change in the CD spectrum, indicating an increased α-helical content most likely due to the elongation in helix IV (3.4.5. Fig. 6.). This helix extension causes a reorientation of several residues, which are involved in target recognition. Particular Phe87 and Phe88, which now point towards the target-binding cleft. The rearrangement of the C-terminal residues Phe87 and Phe88 upon Zn²⁺ binding enlarges the hydrophobic surface of S100B. Such an rearrangement of the hydrophobic residues Phe87 and Phe88 are reasonably for the 5-fold higher affinity of bound TRTK-12 peptide from CapZ to the Zn²⁺-Ca²⁺-S100B, compared to Ca²⁺ -S100B (Barber et al., 1999). Besides this, the binding of Zn²⁺ could also affect the

binding affinity of ligands to S100B in a positive manner by stabilizing the binding site at the C-terminus of S100B and therfor stabilizing the ligand bound S100B complex. A more pronounced effect of sole Zn²⁺-loaded S100B is reflected in the ability of Zn²⁺ -S100B to induce total disassembly of microtubules in the presence of µM Zn²⁺

concentrations were Zn²⁺-S100B leads to an inhibition of τ phosphorylation by protein kinase II (Baudier and Cole, 1988), possibly by Zn²⁺ sequestration. It might be possible that the C-terminus of S100B form a functional Zn²⁺ binding site including the residues Phe87 and Phe88 which can cooperate independently from the Ca²⁺ binding EF-hands, therefore S100B may exert besides a Ca²⁺ dependent function also a Zn²⁺ dependent function, without Ca²⁺. In all these cases, Zn²⁺ binding may enable Ca²⁺-S100B to an additional way to modulate the dissociation rate for bound ligands.

Comparison of the interhelical angles within the three Zn²⁺-Ca²⁺-S100B structures indicates that the angles and distances of the flanking helices of the S100-specific EF-hand are virtually identical (I-II = 137.7 ± 0.4°, 15 Å; III-IV = 106,2 ± 0.8°, 15 Å Table 4 3.4.5.). A difference was detected for the flanking helices III and IV of the classical EF-hand, were the comparison of the human Ca²⁺-S100B crystal structure (2H61) with the human Zn²⁺-Ca²⁺-S100B crystal structures shows only a minor effect. Here, the addition of Zn²⁺ to the Ca²⁺-S100B induces only a small change to a more open conformation, shown by an increase of the interhelical angles between helices III and IV of 2°-3°.

Combined, Zn²⁺ binding does not induce any noteworthy change in the interhelical angles of both EF-hands but it favors an enlargement of the hydrophobic surface at the C-terminus and therefore may contribute to the binding affinity of Zn²⁺-Ca²⁺-S100B to its ligands.

In previous studies, the divalent cation binding properties of the human S100B was studied by Baudier et. al. and it was found that S100B binds four Ca²⁺ and 6-8 Zn²⁺ (two high affinity plus 4-6 low affinity) atoms per dimer. The affinity of S100B for Zn²⁺ is considerably higher than that for Ca²⁺. The binding constant for the Zn²⁺ ion was measured and determined to ~100 nM. (Baudier et al., 1986; Rustandi et al., 1998). The strong binding of the Zn²⁺ to S100B is achieved through four residues of a preformed binding site (3.4.5. Fig.2 A-C). The distance between the two Zn²⁺ ions in the structures is approximately 30.4 Å. Interestingly, alignments of the main-chain atoms (residues 1-89) of human Ca²⁺-S100B subunits with the obtained Zn²⁺-Ca²⁺-S100B structures show no significant changes upon binding of Zn²⁺, neither in the overall structure (not shown) nor in the EF-hand Ca²⁺ binding loops (3.4.5. Fig. 5 B). Crystal structures obtained at pH

-CONCLUSIONS-

124

6.5 and pH 10.0 show two histidines His15, His25 from one subunit and one histidine, His85´ and a Glu89´ from the second subunit involved in coordinating Zn²⁺. The Zn²⁺

coordination is obtained by the imidazoles of the histidines and the terminal carboxylate oxygen atom of the glutamate. The O-Zn and N-Zn distances at the Zn²⁺ binding sites are comparable to other Zn²⁺ binding sites (3.4.5. Table: 4) (Harding, 2000).

Furthermore, the Zn²⁺ binding site ties the two subunits more together, since two of the coordinating ligands of at Zn²⁺ site originate from one subunit and the other ligands are derived from the second subunit (3.4.5. Fig. 2 A-C). Remarkably, in the crystal structure obtained at pH 9.0, the Zn²⁺ ion is coordinated by four histidines (His15, His25, His85´

and His90´). In all three Zn²⁺-Ca²⁺-S100B structures, the Zn²⁺ ligand is coordinated in a slightly distorted tetraeder (3.4.5. Fig. 2 A-C). A similar coordination was shown for Cu²⁺ in the Cu²⁺-Ca²⁺-S100A12 structure by three histidines His15, His85´ and His89´

and Asp25 (Moroz et al., 2003) and for the Zn²⁺-Ca²⁺-loaded S100A7 were Zn²⁺ is coordinated by His15, His85´ and His89´ and Asp25 (Fig 4 A-C). It is proposed that S100B binds Cu²⁺ at the same site. Sequence alignments showed that only the calgranulins S100A8, S100A9 and S100A12, as well as S100B and S100A7 have such a common Zn²⁺-/Cu²⁺-binding motif which is highly conserved (Moroz et al., 2003).

Interestingly, these Zn²⁺ binding S100-proteins have an extracellular function. There they can exert Zn²⁺ dependent function distinct from intracellular functions, in both circumstances, Zn²⁺ binding promotes ligand-binding affinity of S100-proteins. In general, once formed, Zn²⁺ binding site seems to be very stable in S100-proteins, which were shown by previous, and our recent study (pH range 6.5 to 10.0).

Binding of Zn²⁺ induces no conformational change in both EF-hands, (3.4.5. Fig.5 B-C).

Although His25 is located at the S100-specific N-terminal EF-hand the conformation of this EF-hand, remains essentially the same upon Zn²⁺ binding. The 10-fold increase in Ca²⁺ affinity to S100B (Baudier et al., 1986) in the presence of Zn²⁺ is explained in that way that Zn²⁺ binding leads to a pre positioning of the N-terminal EF-hand loop which ease the followed Ca²⁺-binding (3.4.5. Fig. 6 A). One can presume that the N-terminal EF-hand loop is brought into a virtual Ca²⁺ loaded position and therefore promotes the higher binding affinity for Ca²⁺. Alignment of the N-terminal EF-hand of the Cu²⁺-Ca²⁺ -S100A12 with the Zn²⁺-Ca²⁺-S100B showed that in both structures the EF-hand loops are kept in the very same position (3.4.5. Fig. 6 C). The same was shown for the EF-hand region in the S100A7 Zn²⁺-loaded structure (Brodersen et al., 1999). Besides this there was also no structural change observed in the C-terminal classical EF-hand loop. This

indicates that Zn²⁺ binding does not induce any conformational change at the EF-hand regions. So one can presume that the Ca²⁺-loaded N-terminal EF-hand exhibits already an ideal topology and geometry for Ca²⁺ binding and that Zn²⁺ binding occurs mainly because of stability and less because of structural reasons. It is coherent that the binding of Zn²⁺ stabilizes the structure at the Ca²⁺-loaded N-terminal EF-hand, by inducing a more rigid loop conformation that might exhibit a Ca²⁺-loaded like topology, which promotes calcium binding.

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