POLD1/p125 has a common B-family fold, similar to other DNA polymerases (Polα and ε).
  Human POLD1/p125 has a putative nuclear localization signal at the N-terminal end (residues 4-19).
Residues 304-533 contain the exonuclease domain (Figure 2) while residues 579-974 contain the polymerase domain.
The exonuclease domain is a DEDDy-type DnaQ-like domain common to the B-DNA polymerase family.
This domain has a beta hairpin structure that helps in switching between the polymerase and exonuclease active sites in case of nucleotide misincorporation.

Motifs A and C, which are the most conserved of the polymerase domain.
These have 2 catalytic aspartates, in motif A (DXXLYPS, D602) and motif C (DTDS, D757) that bind calcium at the active site.
Motif A has 11 amino acids that are important in nucleotide incorporation and formation of the phosphodiester bond.

Tyrosine Y701 functions similarly to tyrosine Y567 in the RB69 bacteriophage orthologue as the sugar steric gate that prevents ribonucleotide incorporation.
 An LXCXE motif (711 to 715) mediates binding to pRB during the G1 phase of cell cycle.
 The polymerase domain also has a highly conserved KKRY motif (residues 806 to 809) which is important for the binding and catalytic function.
POLD1 can be targeted to the nucleolus upon acidification via a nucleolar detention sequence (NoDS) motif represented by small sequence motifs dispersed throughout the protein coding region.
The C-terminal domain has two conserved cysteine-rich metal-binding motifs (CysA and CysB) (from 1012 and 1083) required for Proliferating Cell Nuclear Antigen (PCNA) binding and recruitment of accessory subunits respectively.
CysB coordinates an [4Fe-4S] cluster added through Cytosolic Iron-sulfur protein Assembly (CIA), which requires the function of the mitochondrial Iron Sulfur Cluster (ISC) assembly machinery.
The maturation process is mediated by the core targeting complex CIA1-CIA2B/FAM96B-MMS19, which interacts with the apoprotein to ensure specific Fe-S cluster insertion.

Binding and association studies have shown that POLD2 is tightly associated with POLD1; POLD3 and POLD2 interact with each other and POLD4 interacts with both POLD1 and POLD2.
Polδ heterotetramer reconstituted by coexpression of subunits in Sf9 cells had properties were similar to Polδ purified from the calf thymus, and the complete holoenzyme was very strongly stimulated by PCNA.
Numerous studies have shown that while POLD1 possesses both the polymerase and the 3’-5’ exonuclease proofreading activity, the other subunits increase these activities, DNA binding abilities, and functionally important interactions with PCNA and its clamp loader Replication Factor C (RFC).
The DNA Polδ holoenzyme is often considered to include PCNA and RFC as well as the four subunits of the polymerase complex (Figure 1).

A number of other studies and screens have identified additional interaction partners relevant to functions in DNA replication and repair.
Figure 3 shows a matrix of established and putative interactions during replication and repair which can be further accessed through  and.
A website at Vanderbilt University provides additional interaction on important POLD1 protein structure and various classes of gene and protein interaction, based on criteria such as co-occurrence in a complex, direct physical interaction, regulatory relationship, and co-expression.
POLD1/p125 has a common B-family fold, similar to other DNA polymerases (Polα and ε).   Human POLD1/p125 has a putative nuclear localization signal at the N-terminal end (residues 4-19). Residues 304-533 contain the exonuclease domain (Figure 2) while residues 579-974 contain the polymerase domain. The exonuclease domain is a DEDDy-type DnaQ-like domain common to the B-DNA polymerase family. This domain has a beta hairpin structure that helps in switching between the polymerase and exonuclease active sites in case of nucleotide misincorporation.
Motifs A and C, which are the most conserved of the polymerase domain. These have 2 catalytic aspartates, in motif A (DXXLYPS, D602) and motif C (DTDS, D757) that bind calcium at the active site. Motif A has 11 amino acids that are important in nucleotide incorporation and formation of the phosphodiester bond.
Tyrosine Y701 functions similarly to tyrosine Y567 in the RB69 bacteriophage orthologue as the sugar steric gate that prevents ribonucleotide incorporation.  An LXCXE motif (711 to 715) mediates binding to pRB during the G1 phase of cell cycle.  The polymerase domain also has a highly conserved KKRY motif (residues 806 to 809) which is important for the binding and catalytic function. POLD1 can be targeted to the nucleolus upon acidification via a nucleolar detention sequence (NoDS) motif represented by small sequence motifs dispersed throughout the protein coding region. The C-terminal domain has two conserved cysteine-rich metal-binding motifs (CysA and CysB) (from 1012 and 1083) required for Proliferating Cell Nuclear Antigen (PCNA) binding and recruitment of accessory subunits respectively. CysB coordinates an [4Fe-4S] cluster added through Cytosolic Iron-sulfur protein Assembly (CIA), which requires the function of the mitochondrial Iron Sulfur Cluster (ISC) assembly machinery. The maturation process is mediated by the core targeting complex CIA1-CIA2B/FAM96B-MMS19, which interacts with the apoprotein to ensure specific Fe-S cluster insertion.
Binding and association studies have shown that POLD2 is tightly associated with POLD1; POLD3 and POLD2 interact with each other and POLD4 interacts with both POLD1 and POLD2. Polδ heterotetramer reconstituted by coexpression of subunits in Sf9 cells had properties were similar to Polδ purified from the calf thymus, and the complete holoenzyme was very strongly stimulated by PCNA. Numerous studies have shown that while POLD1 possesses both the polymerase and the 3’-5’ exonuclease proofreading activity, the other subunits increase these activities, DNA binding abilities, and functionally important interactions with PCNA and its clamp loader Replication Factor C (RFC). The DNA Polδ holoenzyme is often considered to include PCNA and RFC as well as the four subunits of the polymerase complex (Figure 1).
A number of other studies and screens have identified additional interaction partners relevant to functions in DNA replication and repair. Figure 3 shows a matrix of established and putative interactions during replication and repair which can be further accessed through  and. A website at Vanderbilt University provides additional interaction on important POLD1 protein structure and various classes of gene and protein interaction, based on criteria such as co-occurrence in a complex, direct physical interaction, regulatory relationship, and co-expression.
POLD1