Allostery is a biological process in which action, often ligand binding, at one site of the protein alters the function at another site. It provides a mechanism for modulating protein functions in a variety of cellular events ranging from signaling, metabolism, to transcription regulation. Despite the critical role of allostery in biology and intense research during the past few decades, the mechanism of long-range communication through the protein is still elusive. The Escherichia coli biotin protein ligase (BirA) is a bifunctional protein that catalyzes post-translational biotinylation and represses transcription initiation. It serves as a model system to investigate long-range allosteric communication, as binding of the effector molecule, bio-5’-AMP, promotes the repressor complex assembly by enhancing BirA homodimerization occurring at a surface 30Å away. Previous studies have established that disorder-to-order transitions of several loop segments on the ligand binding and dimerization surfaces contribute to BirA allostery. In this dissertation, integrated structural, functional, and computational approaches were used to investigate the molecular mechanisms of allosteric communication between these transitions. Double-mutant cycle analysis demonstrated reciprocal coupling between residues on two distant surfaces, and results of molecular dynamics simulations indicated that functional coupling occurs via modulation of structure and dynamics of surface loops undergo disorder-to-order transitions. Further structural and simulation-based network analyses revealed that these transitions are linked to formation of a residue network, and alanine substitutions of residues at network positions perturb both input (effector binding) and output (dimerization) of allostery. In addition, Force Distribution Analysis showed that perturbed loop folding is associated with redistribution of mechanical stress experienced by network residues. The combined results indicated a mechanism for BirA allosteric regulation in which disorder-to-order transitions and joint network formation enables long-range communication through the protein. Finally, results of functional measurements indicated a conserved allosteric regulation mechanism among Escherichia coli (Ec), Staphylococcus aureus (Sa), and Bacillus subtilis (Bs), as bio-5’-AMP binding to Sa and BsBirA induces homodimerization similar to that observed for EcBirA.