Despite their importance for antibody architecture and design, the principles governing antibody domain stability are still not understood in sufficient detail. Here, to address this question, we chose a domain from the invariant part of IgG, the C_H2 domain. We found that compared with other Ig domains, the isolated C_H2 domain is a surprisingly unstable monomer, exhibiting a melting temperature of ~ 44 °C. We further show that the presence of an additional C-terminal lysine in a C_H2 variant substantially increases the melting temperature by ~ 14 °C relative to C_H2 wt. To explore the molecular mechanism of this effect, we employed biophysical approaches to probe structural features of C_H2. The results revealed that Lys101 is key for the formation of three secondary structure elements: the very C-terminal β-strand and two adjacent α-helices. We also noted that a dipole interaction between Lys101 and the nearby α-helix, is important for stabilizing the C_H2 architecture by protecting the hydrophobic core. Interestingly, this interaction between the α-helix and C-terminal charged residues is highly conserved in antibody domains, suggesting that it represents a general mechanism for maintaining their integrity. We conclude that the observed interactions involving terminal residues have practical applications for defining domain boundaries in the development of antibody therapeutics and diagnostics.