**4. Structural transitions within the AICD**

First structural insights on the AICD peptide came from NMR experiments, revealing most of the AICD to be unstructured. The transient structure (also termed intrinsic disorder: ID) of cytoplasmic domains of membrane proteins is well suited for the molecular recognition in intracellular signaling events for a number of reasons [43]: (i) modulation of the structural propensity provides ID proteins with the capability to combine high specificity with low affinity; (ii) binding diversity in which one region specifically recognizes differently shaped partners by structural accommodation at the binding interface, a phenomenon known as oneto-many signaling; (iii) binding commonality in which distinct sequences recognize a common binding site (with eventually different folds); (iv) the formation of large interaction surfaces as the ID region wraps up or surrounds its binding partner, making it possible to overcome steric restrictions; (v) faster rates of association by reducing dependence on orientation factors and by enlarging target sizes; (vi) faster rates of dissociation by unzipping mechanisms; (vii) the precise control and simple regulation of the binding thermodynamics; and (viii) the reduced life-time of ID proteins in the cell, possibly representing a mechanism of rapid turnover of important regulatory molecules. A prominent example of intrinsically disordered proteins is α-synuclein, a protein critically involved in Parkinson's disease, which binds to a multitude of partners differentially by alternative folding [44], a feature that equally applies to the intracellular domain of APP.

Although NMR experiments revealed the AICD to be intrinsically disordered, the TPEE and NPTY motifs where found to form type I β-turns and TPEE forms part of a helix-capping box [19] (Figure 3). Type I turns are the most frequent reverse turns in protein structures, which in total involve about 1/3rd of all residues. Turns usually occur on the exposed protein surfaces and represent molecular recognition sites. In a capping box, the side chain of the first helical residue forms a hydrogen bond with the backbone of the fourth helical residue and, recipro‐ cally, the side chain of the fourth residue forms a hydrogen bond with the backbone of the first residue [45]. These boxes are known to stabilize the N-termini of α-helices, and preordering of the elements is thought to guide recognition of the intracellular protein network and to reduce the entropic costs for complex formation, a feature that applies as well for APP. In addition, the conformation of the TPEE motif and the propensity of forming the N-terminally capped α helix critically depend on the phosphorylation status of Thr668 [20, 46]. This structure-function relationship can be explored by the study of the AICD with its cytoplasmic interaction partners.

**Figure 3. The TPEE and NPTY motifs.** A. The TPEE motif forms a type I β-turn and a helix capping box with two char‐ acteristic hydrogen bonds (dashed yellow lines). B. The NPTY motif forms a similar type I β-turn.
