The 3,144 amino acid primary huntingtin sequence (by convention Q23-huntingtin) is depicted as a yellow bar with the location of the polyglutamine tract indicated by the green arrowhead (A). The short-, mid- and long-range Lys-Lys cross-links by DSS identified in Q23-huntingtin (above the bar, Q23) and Q78-huntingtin (below the bar, Q78) by XL-MS are depicted by the green, blue and red-colored lines, respectively. Below that is a schematic view of huntingtin with five sub-domains delineated by the shared patterns of intra-molecular interactions; two amino-terminal (NTD-I, NTD-II) and three carboxyl-terminal (CTD-I, UCD and CTD-II), as defined relative to the landmark major protease-sensitive site at ~ residue 1200 identified previously (Seong et al., 2010), which is denoted by the large red arrowhead, while the secondary minor cleavage site is denoted by the small red arrowhead. The cross-links of Q46 huntingtin (Q46) identified in XL-MS analysis are also shown under the five sub-domains schematic. Lys-Lys cross-links by DSS unique to Q23-huntingtin, Q78-huntingtin and Q46-huntingtin are shown in cyan, pink, and orange, respectively in each pair-wise comparison of Q23 vs Q78 (B), Q23 vs Q46 (C) or Q46 vs Q78 (D). The amino-terminal (yellow) and carboxyl-terminal (blue) sub-domains are depicted in cartoons (E) to show more substantial interactions (red thicker dashed arrows) between NTD-I and CTD-I in Q23-huntingtin (left) and between CTD-II and NTD-II or CTD-I in Q78-huntingtin (right) and throughout both amino- and carboxyl-terminal sub-domains in Q46-huntingtin (middle). In all three huntingtins (all red dashed arrows), NTD-I folds to contact CTD-I and CTD-II also contacts CTD-I as well as NTD-II, implying that the physical impact of the polyglutamine tract at the very amino-terminal end has the opportunity to subtly but globally alter the entire huntingtin structure and function in a polyglutamine length-dependent manner.