Way back when I did wing chun, it was as said above, the bottom 3 knuckles.
All my karate training has focused on bare knuckle application using the larger top two (or for a discrete, bullet effect, just the top) knuckles, with a verticle strike and straight line down the forearm. I have been told by those I put faith in that this type of strike is one of the best for reducing chances of broken wrist or knuckles from a bare fisted punch and it feels good for me.
My boxing training (with gloves of course) has different focuses depending on the target and way the target is displayed/accessible. For example, if with a right hook the head of the opponent is not covered up, or not defended well, then I apply a vertical fist blow (base/bottom of hand, ie pinkie at bottom, to floor) - and if the head is better covered, then to get through the defence/smaller opening I turn to a horizontal strike (palm facing down) to temple area etc. With both strikes I still keep the focus on the large two knuckles but actually am fully contacting with all 3 larger knuckles through the gloves.
Uppercuts in gloves are interesting as sometimes, depending on the angle and how close you are in, it can be a hit from either the inside (smaller) or outside knuckles.